Dolastatin 15 derivatives

ABSTRACT

Compounds of the present invention include cell growth inhibitors which are peptides of Formula I, 
     
         A-B-D-E-F-(G).sub.r -(K).sub.s -L                          (I), 
    
     and acid salts thereof, wherein A, B, D, E, F, G and K are α-amino acid residues, and s and r are each, independently, 0 or 1. L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a β-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group. The present invention also includes a method for treating cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition.

BACKGROUND OF THE INVENTION

A number of short peptides with significant activity as inhibitors ofcell growth have been isolated from the Indian Ocean sea hare Dolabellaauricularia (Bai et al., Biochem. Pharmacology,40: 1859-1864 (1990);Beckwith et al., J. Natl. Cancer Inst., 85: 483-488 (1993) andreferences cited therein). These include Dolastatins 1-10 (U.S. Pat. No.4,816,444, issued to Pettit et al.) and Dolastatin-15 (European PatentApplication No. 398558). Dolastatin 15, for example, markedly inhibitsthe growth of the National Cancer Institute's P388 lymphocytic leukemia(PS system) cell line, a strong predictor of efficacy against varioustypes of human malignancies.

The exceedingly small amounts of the various Dolastatin peptides presentin Dolabella auricularia (about difficulties in purifying amountssufficient for evaluation and use, have motivated efforts toward thesynthesis of these compounds (Roux et al., Tetrahedron 50: 5345-5360(1994); Shioiri et al., Tetrahedron 49: 1913-24 (1993); Patino et al.,Tetrahedron 48: 4115-4122 (1992) and references cited therein).Synthetic Dolastatin 15, however, suffers from drawbacks which includepoor solubility in aqueous systems and the need for expensive startingmaterials for its synthesis. These, in turn, have led to the synthesisand evaluation of structurally modified Dolastatin 15 derivatives [cf.:Biorg. Med. Chem. Lett. 4: 1947-50 (1994); WO 93 03054; JP-A-06234790;WO 93 23424].

However, there is a need for synthetic compounds with the biologicalactivity of Dolastatin 15 which have useful aqueous solubility and canbe produced efficiently and economically.

SUMMARY OF THE INVENTION

Compounds of the present invention include cell growth inhibitors whichare peptides of Formula I,

    A-B-D-E-F-(G).sub.r -(K).sub.s -L                          (I),

and acid salts thereof, wherein A, B, D, E, F, G and K are α-amino acidresidues, and s and r are each, independently, 0 or 1. L is a monovalentradical, such as, for example, an amino group, an N-substituted aminogroup, a β-hydroxylamino group, a hydrazido group, an alkoxy group, athioalkoxy group, an aminoxy group, or an oximato group.

Another aspect of the present invention includes pharmaceuticalcompositions comprising a compound of Formula I and a pharmaceuticallyacceptable carrier.

An additional embodiment of the present invention is a method fortreating cancer in a mammal, such as a human, comprising administeringto the mammal an effective amount of a compound of Formula I in apharmaceutically acceptable composition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to peptides having antineoplasticactivity. It also includes pharmaceutical compositions comprising thesecompounds and methods for treating cancer in a mammal, including ahuman, by administration of these compositions to the mammal.

Dolastatin 15, a peptide isolated from the sea hare Dolabellaauricularia, is a potent inhibitor of cell growth. This compound,however, is present in trace quantities in the sea hare, and is thusdifficult to isolate. Dolastatin 15 is also expensive to synthesize andsuffers from poor aqueous solubility. As shown herein, however,Dolastatin 15 can serve as a starting point for the development ofcompounds which overcome these disadvantages while retainingantineoplastic activity or exhibiting greater antineoplastic activitythan the natural product. Applicants have discovered that certainstructural modifications of Dolastatin 15 provide compounds with asurprisingly improved therapeutic potential for the treatment ofneoplastic diseases as compared to Dolastatin 10 and Dolastatin 15.Furthermore, the compounds of the present invention can be convenientlysynthesized, as described below in detail.

For the purposes of the present invention, the term "monovalent radical"is intended to mean an electrically neutral molecular fragment capableof forming one covalent bond with a second neutral molecular fragment.Monovalent radicals include the hydrogen atom, alkyl groups, such asmethyl, ethyl and propyl groups, halogen atoms, such as fluorine,chlorine and bromine atoms, aryl groups, such as phenyl and naphthylgroups, and alkoxy groups, such as methoxy and ethoxy groups. Twomonovalent radicals on adjacent sigma-bonded atoms can also togetherform a pi bond between the adjacent atoms. Two monovalent radicals mayalso be linked together, for example, by a polymethylene unit, to form acyclic structure. For example, the unit --N(R)R', wherein R and R' areeach a monovalent radical, can, together with the nitrogen atom, form aheterocyclic ring. In addition, two monovalent radicals bonded to thesame atom can together form a divalent radical, such as an oxygen atomor an alkylidene group, for example, a propylidene group.

For the purposes of the present invention, the term "normal alkyl"refers to an unbranched, or straight chain, alkyl group, for example,normal propyl (n-propyl, --CH₂ CH₂ CH₃).

The compounds of the present invention can be represented by Formula I,

    A-B-D-E-F-(G).sub.r -(K).sub.s -L                          (I),

wherein A, B, D, E, F, G, and K are α-amino acid residues; s and r areeach, independently, 0 or 1; and L is a monovalent radical such as anamino group, an N-substituted amino group, a β-hydroxylamino group, ahydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group,or an oximato group.

The peptides of Formula I are generally composed of L-amino acids butthey can contain one or more D-amino acids. In the following discussion,reference to a particular amino acid includes both enantiomers unless aspecific enantiomer is indicated. The present compounds can also bepresent as salts with physiologically-compatible acids, includinghydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoricacid, methanesulfonic acid, acetic acid, formic acid, maleic acid,fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid,L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoicacid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.

The following is a description of the present invention, including adetailed description of individual components and of methods of usingthe claimed compounds.

Compounds of the Present Invention

Identity of A

In one embodiment, A is a proline derivative of Formula II_(a), ##STR1##where n_(a) is an integer, preferably 0, 1, 2, or 3. R_(a) is amonovalent radical, such as a hydrogen atom or an unsubstituted orfluorine-substituted alkyl group, for example a normal, branched orcyclic C₁ -C₃ -alkyl group which is, optionally, substituted by from 1to about 3 fluorine atoms; suitable examples include methyl, ethyl,isopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl,1-fluoromethyl-2-fluoroethyl or cyclopropyl; methyl, ethyl or isopropylare preferred;

In this embodiment, R¹ _(a) is a monovalent radical, such as a hydrogenatom, an alkyl group, such as a methyl, ethyl or propyl group, or aphenyl group. The phenyl group can be substituted; suitable substituentsinclude one or more halogen atoms, with fluorine, chlorine and bromineatoms preferred, C₁ -C₄ -alkyl groups, methoxy, ethoxy, trifluoromethylor nitro groups. R_(a) and R¹ _(a) together can also form a propylenebridge.

R² _(a) /R³ _(a) /R⁴ _(a) and R⁵ _(a) are each, independently, amonovalent radical, such as a hydrogen atom or an alkyl, preferably,methyl, group.

In another embodiment, A is a substituted glycine derivative of FormulaIII_(a), ##STR2## where R_(a) has the meaning stated for R_(a) inFormula II_(a) and, R¹ _(a) is a monovalent radical, for example, ahydrogen atom or a C₁ -C₆ -alkyl group, preferably a methyl, ethyl orpropyl group.

In this embodiment, R⁶ _(a) is a monovalent radical, such as an alkyl,substituted alkyl, alkenyl, phenyl or substituted phenyl group. Suitableexamples include methoxymethyl, 1-methoxyethyl,1,1-dimethyl-hydroxymethyl, 1-trifluoromethylethyl,1-trifluoromethyl-2,2,2-trifluoroethyl, vinyl, and 1-methylvinyl. Phenylsubstituents can include one or more halogen atoms, preferably fluorine,chlorine or bromine atoms, and alkyl, methoxy, ethoxy, trifluoromethyl,and nitro groups.

When R¹ _(a) is an alkyl group, R⁶ _(a) can also be a C₁ -C₆ -alkyl,cycloalkyl, unsubstituted benzyl or substituted benzyl group. Suitablebenzyl substituents include one or more halogen atoms, such as fluorine,chlorine or bromine atoms, C₁ -C₄ -alkyl groups, and methoxy, ethoxy,trifluoromethyl and nitro groups.

R⁷ _(a) is a monovalent radical, preferably a methyl, ethyl or isopropylgroup.

In another embodiment, A is an α-amino acid derivative of FormulaIV_(a), ##STR3## where m_(a) is an integer, preferably 1 or 2, and R_(a)and R⁷ _(a) have the meanings stated for these substituents in FormulaIII_(a).

In another embodiment, A is an α-amino acid derivative of Formula V_(a),##STR4## where R_(a) and R⁷ _(a) have the meanings stated for R_(a) andR⁷ _(a) in Formula III_(a).

In a further embodiment, A is a substituted proline derivative ofFormula VI_(a), ##STR5## where R_(a) and R¹ _(a) have the meaningsstated for R_(a) and R¹ _(a) in Formula II_(a), and X_(a) is amonovalent radical, preferably a hydroxyl, alkoxy, for example, methoxyor ethoxy, group or a fluorine atom.

In another embodiment, A is a thiaprolyl derivative of Formula VII_(a),##STR6## where R_(a), R¹ _(a), R² _(a), R³ _(a), R⁴ _(a) and R⁵ _(a)have the meanings stated for the respective substituents in FormulaII_(a).

In another embodiment, A is a 1,3-dihydroisoindole derivative of FormulaVIII_(a) ##STR7## where R_(a) has the meaning stated for R_(a) forFormula II_(a).

In another embodiment, A is a 2-azabicyclo[2.2.1]heptane-3-carboxylicacid derivative of Formula IX_(a), ##STR8## where Z_(a) is a single ordouble bond and R_(a) has the meaning stated for Formula II_(a). The3-carbonyl substituent can have either the exo or endo orientation.

In another embodiment, A is an α-amino acid derivative of Formula X_(a),##STR9## where n_(a) has the meaning as stated for n_(a) for FormulaII_(a), and R⁷ _(a) and R_(a) have the meanings as stated for R⁷ _(a)and R_(a) for Formula III_(a).

Identity of B

B is a valyl, isoleucyl, allo-isoleucyl, norvalyl, 2-tert-butylglycyl or2-ethylglycyl residue. B can also be an α-amino acid residue of FormulaII_(b), ##STR10## in which R¹ _(b) and R² _(b) are each a monovalentradical. R¹ _(b) is, preferably, a hydrogen atom and R² _(b) is, forexample, an alkyl, alkoxyalkyl or alkenyl group. In preferredembodiments, R² _(b) is a cyclopropyl group, a normal or branched butyl,preferably tertiary-butyl, group, a methoxymethyl group, a1-methoxyethyl group or a 1-methylvinyl group. Additionally, R¹ _(b) andR² _(b) together can be an isopropylidene group.

Identity of D

D is an N-alkylvalyl, N-alkyl-2-ethylglycyl, N-alkyl-2-tert-butylglycyl,N-alkyl-norleucyl, N-alkyl-isoleucyl, N-alkyl-allo-isoleucyl orN-alkyl-norvalyl residue, where the N-alkyl group is preferably a methylgroup or an ethyl group.

In another embodiment, D is an α-amino acid residue of Formula II_(d),##STR11## where R_(d) has the meaning stated for R_(a) in FormulaIII_(a), R¹ _(d) is a monovalent radical, preferably a hydrogen atom,and R² _(d) is a monovalent radical, for example, an alkyl, alkoxyalkylor alkenyl group. In preferred embodiments, R² _(d) is a cyclopropylgroup, a normal or branched butyl, preferably tertiary-butyl, group, amethoxymethyl group, a 1-methoxyethyl group or a 1-methylvinyl group.such as a cyclopropyl group, a methoxymethyl group, a 1-methoxyethylgroup or a 1-methylvinyl group. Additionally, R¹ _(d) and R² _(d)together can form an isopropylidene group.

Alternatively, D can be a proline derivative of Formula III_(d),##STR12## where n_(d) is an integer, for example, 1 or 2, and R³ _(d)has the meaning stated for R¹ _(a) in Formula III_(a). X_(d) is amonovalent radical, preferably a hydrogen atom, and, in the case wheren_(d) equals 1, can also be a hydroxy or alkoxy, for example, methoxy orethoxy, group or a fluorine atom.

Identity of E

E is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolylresidue, or a cyclic α-amino carboxylic acid residue of Formula II_(e),##STR13## where n_(e) is an integer, preferably 0, 1 or 2. R¹ _(e) hasthe meaning stated for R¹ _(a) in Formula III_(a). R² _(e) and R³ _(e)are each a monovalent radical, and can be, independently, a hydrogenatom or an alkyl, preferably methyl, group. R⁴ _(e) is a monovalentradical, preferably a hydrogen atom, a hydroxy, alkoxy, for example,methoxy or ethoxy, group or a fluorine atom. R⁵ _(e) is a monovalentradical, preferably a hydrogen atom or a fluorine atom. In the casewhere n_(e) is 1, R³ _(e) and R⁴ _(e) can together form a double bond,or R⁴ _(e) and R⁵ _(e) can together be a double-bonded oxygen radical.In the case where n_(e) has the value 1 or 2, R¹ _(e) and R² _(e) cantogether form a double bond.

In another embodiment, E is a 2- or 3-amino-cyclopentanecarboxylic acidresidue of Formula III_(e), ##STR14## where R_(e) is an alkyl group,such as methyl or ethyl, and R¹ _(e) has the meaning stated for R¹ _(a)in Formula III_(a).

Identity of F

F is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolylresidue. F can also be a cyclic α-amino acid residue of Formula II_(f),##STR15## where n_(f) is an integer, preferably 0, 1 or 2. R¹ _(f) hasthe meaning stated for R¹ _(a) in Formula III_(a). R² _(f) and R³ _(f)are each a monovalent radical, and can be, independently, a hydrogenatom or an alkyl, preferably methyl, group. R⁴ _(f) is a monovalentradical, preferably a hydrogen atom, a hydroxy, alkoxy, for example,methoxy or ethoxy, group or a fluorine atom. R⁵ _(f) is a monovalentradical, preferably a hydrogen atom or a fluorine atom. In the casewhere n_(f) has the value 1, R³ _(f) and R⁴ _(f) together can form adouble bond or R⁴ _(f) and R⁵ _(f) can together be a double-bondedoxygen radical.

In the case where n_(f) has the value 1 or 2, R¹ _(f) and R² _(f) cantogether form a double bond.

In another embodiment, F is a 2- or 3-amino-cyclopentanecarboxylic acidresidue of Formula III_(f) ##STR16## where R_(f) is a monovalentradical, such as a methyl or ethyl group, and R¹ _(f) has the meaningstated for R¹ _(a) in Formula III_(a).

In another embodiment, F is an N-alkylglycyl or N-alkylalanyl residue,and the alkyl group is, preferably, a methyl group or an ethyl group.

Identity of G

G is an α-amino acid residue of Formula II_(g). ##STR17## wherein R¹_(g) is a hydrogen atom, or an alkyl group, for example, methyl, ethylor n-propyl. R² _(g) can be, for example, a hydrogen atom, or an alkyl,arylalkyl, heteroarylalkyl or aryl group. Preferably, R² _(g) is anethyl, isopropyl, tert-butyl, isobutyl, 2-methylpropyl,cyclohexylmethyl, benzyl, thiazolyl-2-methyl, pyridyl-2-methyl, n-butyl,2,2-dimethylpropyl, naphthylmethyl, or n-propyl group, or a substitutedor unsubstituted phenyl group. Suitable phenyl substituents include oneor more halogen, preferably fluorine, chlorine or bromine, atoms, C₁ -C₄-alkyl groups, methoxy, ethoxy, nitro or trifluoromethyl groups or adioxomethylene group. Alternately, R¹ _(g) and R² _(g) can, togetherwith the α-carbon atom, form a cyclopentane or cyclohexane ring or abenzo-fused cyclopentane ring, such as, for example, the indanyl group.

Identity of K

K is an α-amino acid residue of Formula II_(k), ##STR18## wherein R¹_(k) has the identity stated for R¹ _(g) in Formula II_(g), and R² _(k)has the identity stated for R² _(g) in Formula II_(g).

Identity of L

In one embodiment, L is an amino or substituted amino group of FormulaII_(l), ##STR19## where R¹ _(l) is a monovalent radical, such as ahydrogen atom, a normal or branched, saturated or unsaturated C₁ -C₁₈-alkoxy group, a substituted or unsubstituted aryloxy group, asubstituted or unsubstituted aryl-C₁ -C₆ -alkoxy group, or a substitutedor unsubstituted aryloxy-C₁ -C₆ -alkoxy or heteroaryl-C₁ -C₆ -alkoxygroup. The aryl group is preferably a phenyl or naphthyl group. Theheteroaryl group is a 5- or 6-membered, preferably nitrogen-, oxygen- orsulfur-containing, ring system, such as, for example, a heteroaryl groupderived from imidazole, isoxazole, isothiazole, thiazole, oxazole,pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine,indole, benzofuran, benzothiophene, indole, isoindole, indazole,quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran,benzothiazole, oxadiazole, thiadiazole or pyridine. Suitable arylsubstituents include one or more halogen, preferably fluorine, bromineor chlorine, atoms, C₁ -C₄ -alkyl groups, methoxy, ethoxy ortrifluoromethyl groups, a dioxymethylene group or nitro groups.

R² _(l) is a monovalent radical, such as a hydrogen atom, a normal orbranched, saturated or unsaturated C₁ -C₁₈ -alkyl group, a C₃ -C₁₀-cycloalkyl group, a substituted or unsubstituted aryl group, or asubstituted or unsubstituted heteroaryl group. The aryl group ispreferably a phenyl or naphthyl group. The heteroaryl group is a 5- or6-membered, preferably nitrogen-, oxygen- or sulfur-containing, ringsystem, such as, for example, a heteroaryl group derived from imidazole,isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan,pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran,benzothiophene, indole, isoindole, indazole, quinoline, pyridazine,pyrimidine, benzimidazole, benzopyran, benzothiazole,oxadiazole,thiadiazole or pyridine. Suitable aryl substituents includeone or more halogen, preferably fluorine, bromine or chlorine, atoms, C₁-C₄ -alkyl groups, methoxy, ethoxy or trifluoromethyl groups, adioxymethylene group or nitro groups.

R² _(l) can, alternately, be of Formula II_(r), ##STR20## where a_(l) isan integer, such as 0, 1, 2, 3, 4 or 5. R³ _(l) is a monovalent radical,preferably a lower alkyl group, such as a methyl, ethyl, propyl orisopropyl group. R⁴ _(l) is a monovalent radical, which can be asaturated or partially unsaturated carbocyclic system comprising fromabout 3 to about 10 carbon atoms, a substituted or unsubstituted aryl orheteroaryl group, with aryl and heteroaryl and preferred substituentshaving the meaning stated for R² _(l) in Formula II_(l).

R² _(l) can also be a substituent of Formula III_(r),

    --(CH.sub.2).sub.2 --W.sub.l --R.sup.5.sub.l               (III.sub.r),

wherein W_(l) is an oxygen or sulfur atom or an N--R⁶ _(l) group. R⁵_(l) is a monovalent radical, such as a hydrogen atom, a C₁ -C₄ -alkylor C₃ -C₇ -cycloalkyl group or a substituted or unsubstituted aryl orarylmethyl group, with aryl and its preferred substituents having themeaning stated for R² _(l) from Formula II_(l). R⁶ _(l) is a monovalentradical, preferably a hydrogen atom, a C₁ -C₄ -alkyl group or a C₃ -C₇-cycloalkyl group, a C₁ -C₁₈ -alkanoyl group, a benzoyl group or asubstituted or unsubstituted aryl or arylmethyl group, with aryl and itspreferred substituents having the meaning stated for R² _(l) in FormulaII_(l).

R² _(l) can, alternately, be a substituent of Formula IV_(r),

    --(CH.sub.2).sub.b.sbsb.l --Z.sub.l                        (IV.sub.r)

where b_(l) is an integer, preferably 2, 3 or 4. Z_(l) can be amonovalent radical such as a formyl, aminocarbonyl or hydrazinocarbonylgroup, or a cyclic or acyclic acetal or thioacetal group.

R² _(l) can also be a substituent of Formula V_(r), ##STR21## in whichb_(l) has the above-mentioned meaning. R⁷ _(l) can be a monovalentradical, such as a polyglycol group of the formula --O--(CH₂ --CH₂--O)_(d).spsb.l --CH₃, where d, is an integer, preferably in the rangefrom about 2 to about 4 or from about 40 to about 90.

R² _(l) can further be a carbohydrate of Formula VI_(r), ##STR22## whereR⁸ _(l) is a monovalent radical, such as a hydrogen atom, a C₁ -C₄-alkanoyl or alkyl group, a benzoyl group or a benzyl group.

L can also be a β-hydroxylamino group of Formula III_(l), ##STR23##where R⁹ _(l) is a monovalent radical such as a hydrogen atom, a C₁ -C₆-alkyl group or a substituted or unsubstituted aryl group, with aryl andits preferred substituents having the meaning stated for R.sup._(l). R¹⁰_(l) is a monovalent radical, preferably a hydrogen atom, alkyl, forexample, methyl, or a phenyl group.

When r and/or s is 1, L can also be an amino group of Formula IV_(l),##STR24## where R² _(l) and R⁴ _(l) are each a monovalent radical. R²_(l) and R⁴ _(l) can also be linked by a carbon-carbon bond.

Another subclass of compounds of this invention includes peptides ofFormula I wherein L is a hydrazido group of Formula V_(l), ##STR25## andR¹¹ _(l) is a monovalent radical, preferably a hydrogen atom. R¹² _(l)can be a monovalent radical such as a hydrogen atom, a normal orbranched C₁ -C₈ -alkyl group, a C₃ -C₈ -cycloalkyl group, a C₃ -C₈-cycloalkyl-C₁ -C₄ -alkyl group or a substituted or unsubstituted aryl,heteroaryl, aryl-C_(l) -C₄ -alkyl or heteroaryl-C₁ -C₄ -alkyl group,where aryl, heteroaryl and their preferred substituents can be selectedfrom among the options listed for R² _(l).

When r and/or s is 1, R¹¹ _(l) can also be selected from among theoptions listed above for R¹² _(l), and the two radicals together canadditionally form a propylene or butylene bridge.

Another subclass of compounds of this invention includes peptides ofFormula I wherein L is a monovalent radical of the formula --O--R¹³ _(l)or the formula --S--R¹³ _(l), where R¹³ _(l) is a monovalent radical,such as a C₃ -C₁₀ -cycloalkyl group, a normal or branched C₂ -C₁₆-alkenylmethyl group or a C₁ -C₁₆ -alkyl group which can be substitutedby from 1 to about 5 halogen, preferably fluorine, atoms.

R¹³ _(l) can also be the radical --(CH₂)_(e) --R¹⁴ _(l), where e is aninteger, preferably 1, 2 or 3. R¹⁴ _(l) is a monovalent radical,preferably a saturated or partially unsaturated C₃ -C₁₀ -carbocycle.

R¹³ _(l) can further be the monvalent radical --[CH₂ --CH═C(CH₃)--CH₂]_(f) --H, where f is an integer, preferably 1, 2, 3 or 4.

R¹³ _(l) can also be the radical --[CH₂ --CH₂ --O]_(g) --CH₃, where g isan integer, preferably in the range from 1 to about 5.

R¹³ _(l) can also be the radical --(CH₂)_(h) -aryl or --(CH₂)_(h)-heteroaryl, where aryl and heteroaryl can also be substituted and,along with their preferred substituents, can be selected from the grouplisted for R² _(l). h is an integer, preferably 0, 1, 2 or 3.

R¹³ _(l) can further be the radical --(CH₂)_(b) --W_(l) --R⁵ _(l). b,W_(l) and R⁵ _(l) can each be selected from among the options describedfor Formula IV_(l).

Another subclass of compounds of this invention includes peptides ofFormula I in which L is an aminoxy group of the formula --O---N(R¹⁵_(l))(R¹⁶ _(l)), where R¹⁵ _(l) and R¹⁶ _(l) are each a monovalentradical, which can independently be a hydrogen atom, a normal orbranched C₁ -C₈ -alkyl group, which can be substituted by halogen,preferably fluorine, atoms, a C₃ -C₈ -cycloalkyl group, a C₃ -C₈-cycloalkyl-C₁ -C₄ -alkyl group, a substituted or unsubstituted aryl orheteroaryl group or a substituted or unsubstituted aryl-C₁ -C₄ -alkylgroup. Aryl and heteroaryl groups and the preferred substituents thereofcan be selected from the options listed for R² _(l). R¹⁶ _(l) can beselected from among the options listed for R¹⁵ _(l). Additionally, R¹⁵_(l) and R¹⁶ _(l) can together form a 5-, 6- or 7-membered heterocycle.The compounds of the present invention further comprise the salts of thecompounds described above with physiologically tolerated acids.

Another subclass of compounds of this invention includes peptides ofFormula I wherein L is an oximato group of the formula --O--N═C(R¹⁵_(l))(R¹⁶ _(l)), R¹⁵ _(l) and R¹⁶ _(l) can be selected from among theoptions listed above and, additionally, can together form a cyclicsystem comprising, preferably, from about 3 to about 7 ring atoms. Thiscyclic system can additionally be fused to one or more aromatic rings.Particularly preferred cyclic systems are shown below. ##STR26##

In one embodiment, the invention provides compounds of Formula I whereinA is an amino acid derivative selected from among N-alkyl-D-prolyl,N-alkyl-L-prolyl, N-alkyl-D-piperidine-2-carbonyl,N-alkyl-L-piperidine-2-carbonyl, N,N-dialkyl-D-2-ethyl-2-phenylglycyland N,N-dialkyl-L-2-ethyl-2-phenylglycyl, wherein alkyl is methyl, ethylor isopropyl; and B is a valyl, isoleucyl or 2-t-butyl-L-glycyl residue.

Preferred compounds of the invention include compounds of Formula Iwherein r and s are each 0. A is an amino acid derivative selected fromamong D-N-methyl-piperidine-2-carbonyl,L-N-methyl-piperidine-2-carbonyl, N,N-dimethylamino-isobutyryl,N-methyl-L-prolyl, N-methyl-L-thiazolidine-4-carbonyl,N,N-dimethylglycyl, L-prolyl, L-piperidine-2-carbonyl,N-propyl-D-piperidine-2-carbonyl, D-piperidine-2-carbonyl,N-ethyl-D-piperidine-2-carbonyl,N-methyl-[2,2,5,5-tetramethyl]-L-thiazolidine-2-carbonyl,N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2-cyclopropylglycyl,N,N-dimethyl-L-2-ethyl-2-phenylglycyl,N,N-dimethyl-D-2-ethyl-2-phenylglycyl, D-prolyl, N-methyl-D-prolyl,N,N-dimethyl-2-(2-fluorophenyl)glycyl,1-aza-[3,3,0]bicyclooctyl-5-carbonyl,N,N-dimethyl-2-[4-fluoro]phenyl-glycyl,N-methyl-[2,2,5,5-tetramethyl]-thiazolidine-2-carbonyl,2-(R,S)-ethyl-2-phenylglycyl, D,L-1-aminoindane-1-carbonyl,N,N-dimethyl-2-(R,S)-methyl-2-phenylglycyl,2-[N,N-dimethylamino]indane-2-carbonyl,5-[N,N-dimethylamino]-5,6,7,8-tetrahydro-naphthalene-5-carbonyl,N-isopropyl-2-(R,S)-ethyl-2-phenylglycyl,1-[N,N-dimethylamino]indane-2-carbonyl,N,N-dimethyl-2-propyl-2-phenylglycyl,N,N-dimethyl-2-[4-methoxy]phenyl-glycyl, N-methyl-3-hydroxy-D,L-valyl,N,N-dimethyl-D,L-2-isopropyl-2-phenylglycyl,N-methylpiperidine-2-carbonyl, N-methyl-L-prolyl,N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl,N-methylazetidine-2-carbonyl, N-isopropylazetidine-2-carbonyl,N,N-dimethyl-[O-methyl]seryl, N,N-dimethyl-[O-methyl]threonyl,N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl,1-[N,N-dimethylamino]cyclohexyl-1-carbonyl,1-[N,N-dimethylamino]cyclopentyl-1-carbonyl and1,2,3,4-tetrahydroisoquinoline-3-carbonyl. B is valyl, isoleucyl or2-tert-butylglycyl. D is N-methylvalyl, N-methyl-2-t-butylglycyl orN-methylisoleucyl. E and F are each, independently, prolyl, thiaprolyl,homoprolyl, hydroxyprolyl, 3,4-didehydroprolyl, 4-fluoroprolyl, and3-methylprolyl. L is an alkoxy group or an amino group of the formula R¹_(l) --N--R² _(l), wherein R¹ _(l) and R² _(l) are independentlyselected from the group consisting of hydrogen, alkoxy, hydroxy, alkyland alkylaryl.

In a particularly preferred subset of the compounds of the invention, rand s are each 0. A is an amino acid derivative selected from amongD-N-methyl-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl,N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2-cyclopropyl-glycyl,N-methyl-D-prolyl, 1-aza-[3,3,0]bicyclooctyl-5-carbonyl,N-methyl-[2,2,5,5-tetramethyl]-thiazolidine-2-carbonyl,2-(R,S)-ethyl-2-phenylglycyl, D,L-1-aminoindane-1-carbonyl,N,N-dimethyl-2-(R,S)-methyl-2-phenylglycyl,5-[N,N-dimethylamino]-5,6,7,8-tetrahydro- naphthalene-5-carbonyl,1-[N,N-dimethylamino]indane-2-carbonyl,N,N-dimethyl-2-propyl-2-phenylglycyl,N,N-dimethyl-L-2-ethyl-2-phenylglycyl,N,N-dimethyl-D-2-ethyl-2-phenylglycyl, N-methyl-3-hydroxy-D,L-valyl,N,N-dimethyl-D,L-2-isopropyl-2-phenylglycyl,N-methyl-piperidine-2-carbonyl, N-methyl-D,L-prolyl,N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl,N-methylazetidine-2-carbonyl, N-isopropylazetidine-2-carbonyl,N,N-dimethyl-[O-methyl]seryl, 1-[N,N-dimethylamino]cyclohexyl-1-carbonyland 1-[N,N-dimethylamino]cyclopentyl-1-carbonyl. B is valyl; D isN-methylvalyl; and E and F are each prolyl. L is a C₁ -C₆ -alkoxy groupor an amino group of the formula R¹ _(l) --N--R² _(l), wherein R¹ _(l)and R² _(l) are each independently selected from the group consisting ofhydrogen, C₁ -C₆ -alkoxy, hydroxy, normal, cyclic or branched C₁ -C₁₂-alkyl, and phenylalkyl.

Synthetic Methods

The compounds of the present invention can be prepared by known methodsof peptide synthesis. Thus, the peptides can be assembled sequentiallyfrom individual amino acids or by linking suitable small peptidefragments. In sequential assembly, the peptide chain is extendedstepwise, starting at the C-terminus, by one amino acid per step. Infragment coupling, fragments of different lengths can be linkedtogether, and the fragments in turn can be obtained by sequentialassembly from amino acids or by fragment coupling of still shorterpeptides.

In both sequential assembly and fragment coupling it is necessary tolink the units by forming an amide linkage, which can be accomplishedvia a variety of enzymatic and chemical methods. Chemical methods forforming the amide linkage are described in detail in standard referenceson peptide chemistry, including Muller, Methoden der organischen ChemieVol. XV/2, 1-364, Thieme Verlag, Stuttgart, (1974); Stewart and Young,Solid Phase Peptide Synthesis, 31-34 and 71-82, Pierce Chemical Company,Rockford, Ill. (1984); Bodanszky et al., Peptide Synthesis, 85-128, JohnWiley & Sons, New York, (1976). Preferred methods include the azidemethod, the symmetric and mixed anhydride method, the use of in situgenerated or preformed active esters, the use of urethane protectedN-carboxy anhydrides of amino acids and the formation of the amidelinkage using coupling reagents, such as carboxylic acid activators,especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide(DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), pivaloylchloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(EDCI), n-propanephosphonic anhydride (PPA),N,N-bis(2-oxo-oxazolidinyl)amidophosphoryl chloride (BOP--Cl),bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBrop),diphenylphosphoryl azide (DPPA), Castro's reagent (BOP, PyBop),O-benzotriazolyl-N,N,N',N'-tetramethyluronium salts (HBTU),O-azabenzotriazolyl-N,N,N',N'-tetramethyluronium salts (HATU),diethylphosphoryl cyanide (DEPCN),2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene dioxide (Steglich'sreagent; HOTDO), and 1,1'-carbonyldiimidazole (CDI). The couplingreagents can be employed alone or in combination with additives such asN,N-dimethyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt),N-hydroxyazabenzotriazole (HOAt), N-hydroxybenzotriazine (HOOBt),N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.

Although the use of protecting groups is generally not necessary inenzymatic peptide synthesis, reversible protection of reactive groupsnot involved in formation of the amide linkage is necessary for bothreactants in chemical synthesis. Three conventional protective grouptechniques are preferred for chemical peptide synthesis: thebenzyloxycarbonyl (Z), the t-butoxycarbonyl (Boc) and the9-fluorenylmethoxycarbonyl (Fmoc) techniques. Identified in each case isthe protective group on the α-amino group of the chain-extending unit. Adetailed review of amino-acid protective groups is given by Muller,Methoden der organischen Chemie Vol. XV/1, pp 20-906, Thieme Verlag,Stuttgart (1974). The units employed for assembling the peptide chaincan be reacted in solution, in suspension or by a method similar to thatdescribed by Merrifield, J. Am. Chem. Soc. 85: (1963) 2149.

Solvents suitable for peptide synthesis include any solvent which isinert under the reaction conditions, especially water,N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile,dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THF),N-methyl-2-pyrrolidone (NMP) and mixtures of these solvents.

Peptide synthesis on the polymeric support can be carried out in asuitable inert organic solvent in which the amino acid derivativesstarting materials are soluble. However, preferred solvents additionallyhave resin- swelling properties, such as DMF, DCM, NMP, acetonitrile andDMSO, and mixtures of these solvents. Following synthesis, the peptideis removed from the polymeric support. The conditions under which thiscleavage is accomplished for various resin types are disclosed in theliterature. The cleavage reactions most commonly used are acid- orpalladium-catalyzed, the former being conducted in, for example, liquidanhydrous hydrogen fluoride, anhydrous trifluoromethanesulfonic acid,dilute or concentrated trifluoroacetic acid, and aceticacid/dichloromethane/trifluoroethanol mixtures. The latter can becarried out in THF or THF-DCM-mixtures in the presence of a weak base,such as morpholine. Certain protecting groups are also cleaved off underthese conditions.

Partial deprotection of the peptide may also be necessary prior tocertain derivatization reactions. For example, peptides dialkylated atthe N-terminus can be prepared by coupling the appropriateN,N-di-alkylamino acid to the peptide in solution or on the polymericsupport, by reductive alkylation of the resin-bound peptide in DMF/1%acetic acid with NaCNBH₃ and the appropriate aldehyde or byhydrogenation of the peptide in solution in the presence of theappropriate aldehyde or ketone and Pd/carbon.

The various non-naturally occurring amino acids as well as the variousnon-amino acid moieties disclosed herein can be obtained from commercialsources or synthesized from commercially available staring materialsusing methods known in the art. For example, amino acid building blockswith R¹ and R² groups can be prepared according to the method describedby Wuensch and Weyl, Methoden der Organische Chemie, vol. XV, SpringerVerlag: Stuttgart, p. 306 (1974) and references cited therein.

Methods of Use of the claimed Compounds

In another embodiment, the present invention comprises a method forpartially or totally inhibiting formation of, or otherwise treating(e.g., reversing or inhibiting the further development of) solid tumors(e.g., tumors of the lung, breast, colon, prostate, bladder, rectum, orendometrial tumors) or hematological malignancies (e.g., leukemias,lymphomas) in a mammal, for example, a human, by administering to themammal a therapeutically effective amount of a compound or a combinationof compounds of Formula I. The compound(s) may be administered alone orin a pharmaceutical composition comprising the compound(s) and anacceptable carrier or diluent. Administration can be by any of the meanswhich are conventional for pharmaceutical, preferably oncological,agents, including oral and parenteral means, such as subcutaneously,intravenously, intramuscularly and intraperitoneally, nasally orrectally. The compounds may be administered alone or in the form ofpharmaceutical compositions containing a compound or compounds ofFormula I together with a pharmaceutically accepted carrier appropriatefor the desired route of administration. Such pharmaceuticalcompositions may be combination products, i.e., they may also containother therapeutically active ingredients.

The dosage to be administered to the mammal, such as a human, willcontain a therapeutically effective amount of a compound describedherein. As used herein, "therapeutically effective amount" is an amountsufficient to inhibit (partially or totally) formation of a tumor or ahematological malignancy or to reverse development of a solid tumor orother malignancy or prevent or reduce its further progression. For aparticular condition or method of treatment, the dosage is determinedempirically, using known methods, and will depend upon factors such asthe biological activity of the particular compound employed; the meansof administration; the age, health and body weight of the recipient; thenature and extent of the symptoms; the frequency of treatment; theadministration of other therapies; and the effect desired. A typicaldaily dose will be from about 0.05 to about 50 milligrams per kilogramof body weight by oral administration and from about 0.01 to about 20milligrams per kilogram of body weight by parenteral administration.

The compounds of the present invention can be administered inconventional solid or liquid pharmaceutical administration forms, forexample, uncoated or (film-)coated tablets, capsules, powders, granules,suppositories or solutions. These are produced in a conventional manner.The active substances can for this purpose be processed withconventional pharmaceutical aids such as tablet binders, fillers,preservatives, tablet disintegrants, flow regulators, plasticizers,wetting agents, dispersants, emulsifiers, solvents, sustained releasecompositions, antioxidants and/or propellant gases (cf. H. Sucker etal.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). Theadministration forms obtained in this way typically contain from about 1to about 90% by weight of the active substance.

The present invention will now be illustrated by the following examples,which are not limiting.

EXAMPLES

The proteinogenous amino acids are abbreviated in the examples using theknown three-letter code. Other abbreviations employed are:TFA=trifluoroacetic acid, Ac=acetic acid, DCM=dichloromethane,DMSO=dimethylsulfoxide, Bu=butyl, Et=ethyl, Me=methyl, Bzl=benzyl. Inthe compounds listed, all proteinogenous amino acids are L-amino acidsunless otherwise noted. Other abbreviations used: Me₂Val=N,N-dimethylvaline, MeVal=N-methylvaline, Bn=benzyl, Me₂Aib=[2-N,N-dimethylamino]-isobutyric acid.

General Procedures

The peptides of the invention are synthesized either by classicalsolution synthesis using standard Z- and Boc-methodology as describedabove or by standard methods of solid-phase synthesis using Boc and Fmocprotective group techniques.

In the case of solid phase synthesis, the N,N-dialkyl-penta- orhexapeptide acids are liberated from the solid support and furthercoupled with the corresponding C-terminal amines in solution. BOP--Cland PyBrop were used as reagents for coupling of the amino acidfollowing the N-methylamino acids. The reaction times werecorrespondingly increased. For reductive alkylation of the N-terminus,the peptide-resin was deprotected at the N terminus and then reactedwith a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acidwith addition of 3 equivalents of NaCNBH₃. After the reaction wascomplete (negative Kaiser test) the resin was washed several times withwater, isopropanol, DMF and dichloromethane.

In solution synthesis, the use of either Boc-protected amino acid NCAs(N-tert.-butyloxycarbonyl-amino acid-N-carboxy-anhydrides), Z-protectedamino acid NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides),or the use of pivaloyl chloride as condensing agent respectively is mostadvantageous for coupling of the amino acid following the N-methylaminoacids. Reductive alkylation of the N terminus can e.g. be achieved byreaction of the N-terminally deprotected peptides or amino acids withthe corresponding aldehydes or ketones using NaCNBH₃ or hydrogen-Pd/C.

Valyl-N-methylvalyl-prolyl-prolylbenzylamide hydrochloride for examplewas prepared according to methods disclosed in German Patent ApplicationNo. DE 19527575 A1.

Purification and characterization of the peptides

Peptide purification was carried out by gel chromatography (SEPHADEXG-10, G-15/10% HOAc, SEPHADEX LH₂ 0/MeOH), medium pressurechromatography (stationary phase: HD-SIL C-18, 20-45 micron, 100Angstrom; mobile phase: gradient with A=0.1% TFA/ MeOH, B=0.1%TFA/water), preparative HPLC (stationary phase: Waters Delta-Pak C-18,15 micron, 100 Angstrom; mobile phase: gradient with A=0.1% TFA/MeOH,B=0.1% TFA/water), or by crystallization.

The purity of the resulting products was determined by analytical HPLC(stationary phase: 100 2.1 mm VYDAC C-18, 5 micron, 300 A; mobile phase:acetonitrile-water gradient, buffered with 0.1% TFA, 40° C.; or 3.9 mmVYDAC C-18, 30° C.).

Characterization was by fast atom bombardment mass spectroscopy andNMR-spectroscopy.

Example 1

Synthesis of [N-Methyl-L-piperidine-2-carbonyl]-Val-MeVal -Pro-Pro-NHBn(Compound 1) and [N-Methyl-D-piperidine-2-carbonyl]-Val-MeVal-Pro-Pro-NHBn (Compound 2)

Preparation of N-methyl-piperidine-2-carboxylic acid

N-Methyl-piperidine-2-carboxylic acid ethyl ester (5.1 g) was dissolvedin a mixture of 100 ml methanol and 10 ml water. NaOH (8 g) was addedand the reaction mixture was stirred at room temperature overnight. Thesolution was then neutralized with hydrochloric acid, evaporated todryness, and evaporated four times with toluene. The resulting powderyresidue was used directly in the next step.

Preparation of [N-Methyl-piperidine-2-carbonyl]-Val-MeVal-Pro-Pro-NHBn

The residue prepared as described above (5.05 g) andH-Val-MeVal-Pro-Pro-NHBn×HCl (4.88 g) were dissolved in 50 ml dry DMF.After cooling the solution in an ice bath, 1.52 g DEPCN and 2.66 mltriethylamine were added. The reaction mixture was stirred at 0° C. for2 h and then at room temperature overnight. The DMF was removed byevaporation under reduced pressure. The residue was diluted withdichloromethane and the organic phase was washed with aqueoushydrochloric acid (pH 2) and water, dried over sodium sulfate andevaporated to dryness. The diastereomeric mixture was then separated byflash chromatography with a gradient using heptane/ethyl acetate anddichloromethane/methanol. Under the HPLC conditions described in theprevious section (C-18 reverse phase) isomer 1 has a retention time of14.9 minutes, and isomer 2 has a retention time of 15.8 minutes. Bothisomers were characterized by fast atom bombardment mass spectrometry([M+H]+=639).

Example 2

Preparation of Me₂ Aib-Val-MeVal-Pro-Pro-NHBn (Compound 3)

Preparation of 2-[N,N-dimethylamino]-isobutyric acid

2-Amino-isobutyric acid (10.3 g) was dissolved in 200 ml methanol. Afteraddition of 25 ml aqueous formaldehyde and 1 g 10% Pd/C, the reactionmixture was hydrogenated overnight at room temperature. The catalyst wasfiltered, and the filtrate was evaporated to dryness. The residue wascrystallized from isopropanol to give 4.8 g of the desired product.

Preparation of Me₂ Aib-Val-MeVal-Pro-Pro-NHBn×HCl

2-[N,N-Dimethylamino]-isobutyric acid (1.3 g, 10 mmol) and 5.5 g (10mmol) H-Val-MeVal-Pro-Pro-NHBn×HCl were dissolved in 50 ml dry DMF.After cooling to 0° C., 1.6 g DEPCN (10 mmol) and 2.9 ml triethylaminewere added to the reaction mixture. The resulting mixture was stirred at0° C. for 2 h and at room temperature overnight. Ice water (50 mL) wasthen added, and the resulting mixture was extracted twice with diethylether. The ether extracts were washed with 1 N NaOH (1×) and aqueousNaCl (3×), then dried over sodium sulfate and evaporated to drynessunder reduced pressure. The product was crystallized from 100 ml diethylether with HCl/ether, and recrystallized from acetone to give 1.2 g ofthe desired product, which was characterized by fast atom bombardmentmass spectrometry ([M+H]+=627).

Example 3

Preparation of [N,N-dimethyl-2-ethyl-2-phenylglycyl]-Val-MeVal-Pro-Pro-NHBn×HCl (Compound 4)

Preparation of[N,N-dimethyl-2-ethyl-2-phenylglycyl]-Val-MeVal-Pro-Pro-NHBn×HCl

2.07 g (10 mmol) N,N-Dimethyl-2-ethyl-2-phenylglycine and 5.5 g (10mmol) H-Val-MeVal-Pro-Pro-NHBn×HCl were dissolved in 100 ml dry DMF.After cooling to 0° C., 1.6 g DEPCN (10 mmol) and 2.9 ml triethylaminewere added. The reaction mixture was stirred at 0° C. for 2 h and atroom temperature overnight, then worked up as described above. The crudeproduct was crystallized from diethyl ether with HCl/ether to give 4 gof the desired product, which was characterized by fast atom bombardmentmass spectrometry ([M+H]+=703).

Example 4

Preparation of [N-Methyl-D-Pro]-Val-MeVal-Pro-Pro-NHBn (Compound 5)

Preparation of Z-D-Pro-Val-MeVal-Pro-Pro-NHBn

3.74 g Z-D-Pro-OH (15 mmol, BACHEM) and 8.25 gH-Val-MeVal-Pro-Pro-NHBn×HCl (15 mmol) were dissolved in 80 ml dry DMF.After cooling to 0° C., 2.4 g DEPCN (2.25 ml, 15 mmol) and 4.2 mltriethylamine (30 mmol) were added. The reaction mixture was stirred at0° C. for several hours and room temperature overnight, then the DMF wasevaporated under reduced pressure. The residue was diluted with ethylacetate and thoroughly washed with dilute aqueous HCl (pH 2), water,dilute aqueous NaOH (pH 9-10), and water. The organic phase was driedover sodium sulfate and evaporated to dryness to yield 9.2 g of thedesired protected pentapeptide.

Preparation of D-Pro-Val-MeVal-Pro-Pro-NHBn×HCl

8.2 g (11 mmol) Z-D-Pro-Val-MeVal-Pro-Pro-NHBn was dissolved in 70 mlmethanol. After addition of 0.7 ml concentrated hydrochloric acid and0.3 g 10% Palladium/charcoal to the solution, the resulting mixture washydrogenated. Filtration and evaporation of the solvent gave a residuewhich was dissolved in water, adjusted to pH 2 and extracted twice withethyl acetate. The aqueous phase was adjusted to pH 9-10 and extractedtwice with dichloromethane. The organic extracts were evaporated and theresidue was redissolved in diethylether and crystallized by addition ofHCl/ether as the hydrochloride salt to give 6.5 g of the desiredproduct.

Preparation of [N-methyl-D-Pro]-Val-MeVal-Pro-Pro-NHBn×HCl

1.94 g (3 mmol) of D-Pro-Val-MeVal-Pro-Pro-NHBn×HCl was dissolved in 30ml methanol. To this solution was then added 0.3 g 10% Pd/charcoal and1.5 ml aqueous formaldehyde solution and the reaction mixture washydrogenated. Following filtration and evaporation of the solvents, theresulting residue was dissolved in water, adjusted to pH 2 and extractedtwice with diethyl ether and several additional times withdichloromethane. The aqueous phase was adjusted to pH 9-10 and extractedtwice with dichloromethane. The organic extracts were dried over sodiumsulfate and evaporated to dryness. The residue was crystallized as thehydrochloride salt to give 0.5 g of the desired product which wascharacterized by fast atom bombardment mass spectrometry ([M+H]+=625).

The compounds listed in Table 1 were prepared according to the methodsdescribed in Examples 1-4. Where compounds are referred to as "isomer 1"or "isomer 2", isomer 1 is the diastereomer with the shorter retentiontime on the reversed phase analytical HPLC system. Fast atombombardment-mass spectrometry results for selected compounds areprovided in Table 2. The compounds presented in Examples 1-4 and Table 1correspond to the indicated sequences:

Compounds 1-5, 7, 9, 10, 12-19, 22-44, 46, 47, 49, 50, 54-59, 61-65,67-108, 119-142, 144, 145, 147, 148, 150, 151, 153, 154, 156, 157, 159,160, 162, 163, 165, 166, 168, 169: SEQ ID NO: 1;

Compounds 170-175: SEQ ID NO: 2;

Compounds 6, 8, 20, 45, 48, 51-53, 60, 66, 109-118, 143, 146, 149, 152,155, 158, 161, 164, 167, 170, 173: SEQ ID NO.: 3;

Compound 11: SEQ ID NO.: 4;

Compound 21: SEQ ID NO: 5.

                  TABLE 1                                                         ______________________________________                                        Compound                                                                                   No.                                                                 - 6        Xah Val Xaa Pro Xab                                                - 7        Xai Val Xaa Pro Xab                                                - 8        Xae Val Xaa Pro Xab                                                - 9        Xad Val Xaa Pro Xbr                                                - 10       Xam Val Xaa Pro Xab                                                - 11       Xaw Ile Xaa Pro Xbx                                                - 12       Xao Val Xaa Pro Xab                                                - 13       Xad Val Xaa Pro Xap                                                - 14       Xaq Val Xaa Pro Xab                                                - 15       Xar Val Xaa Pro Xab                                                - 16       Xas Val Xaa Pro Xab                                                - 17       Xat Val Xaa Pro Xab isomer 1                                       - 18       Xat Val Xaa Pro Xab isomer 2                                       - 19       Xaf Val Xaa Pro Xab                                                - 20       Xav Val Xaa Pro Xab                                                - 21       Xag Val Xaa Pro Xab                                                - 22       Xax Val Xaa Pro Xab isomer 1                                       - 23       Xax Val Xaa Pro Xab isomer 2                                       - 24       Xay Val Xaa Pro Xab                                                - 25       Xaz Val Xaa Pro Xab isomer 1                                       - 26       Xaz Val Xaa Pro Xab isomer 2                                       - 27       Xba Val Xaa Pro Xab                                                - 28       Xbb Val Xaa Pro Xab                                                - 29       Xbc Val Xaa Pro Xab                                                - 30       Xbd Val Xaa Pro Xab isomer 1                                       - 31       Xbd Val Xaa Pro Xab isomer 2                                       - 32       Xbe Val Xaa Pro Xab isomer 1                                       - 33       Xbe Val Xaa Pro Xab isomer 2                                       - 34       Xbf Val Xaa Pro Xab isomer 1                                       - 35       Xbg Val Xaa Pro Xab                                                - 36       Xbh Val Xaa Pro Xab isomer 1                                       - 37       Xbh Val Xaa Pro Xab isomer 2                                       - 38       Xbi Val Xaa Pro Xab isomer 1                                       - 39       Xbi Val Xaa Pro Xab isomer 2                                       - 40       Xbk Val Xaa Pro Xab isomer 1                                       - 41       Xbk Val Xaa Pro Xab isomer 2                                       - 42       Xbl Val Xaa Pro Xab                                                - 43       Xbf Val Xaa Pro Xab isomer 2                                       - 44       Xbm Val Xaa Pro Xab                                                - 45       Xaw Val Xaa Pro Xbn                                                - 46       Xbo Val Xaa Pro Xbn isomer 1                                       - 47       Xbo Val Xaa Pro Xbn isomer 2                                       - 48       Xaw Val Xaa Pro Xbp                                                - 49       Xbo Val Xaa Pro Xbp isomer 1                                       - 50       Xbo Val Xaa Pro Xbp isomer 2                                       - 51       Xaw Val Xaa Pro Xbq                                                - 52       Xaw Val Xaa Pro Xbr                                                - 53       Xbs Val Xaa Pro Xbt isomer 1                                       - 54       Xbl Val Xaa Pro Xab isomer 1                                       - 55       Xbl Val Xaa Pro Xab isomer 2.                                      - 56       Xbu Val Xaa Pro Xab isomer 1                                       - 57       Xbv Val Xaa Pro Xab -  - 58       Xbw Val Xaa Pro Xab                       isomer 1                                                             - 59       Xbw Val Xaa Pro Xab isomer 2                                       - 60       Xbs Val Xaa Pro Xbt isomer 2                                       - 61       Xbu Val Xaa Pro Xab isomer 2                                       - 62       Xbo Val Xaa Pro Xbr isomer 1                                       - 63       Xbo Val Xaa Pro Xbr isomer 2                                       - 64       Xbo Val Xaa Pro Xbq isomer 1                                       - 65       Xbo Val Xaa Pro Xbq isomer 2                                       - 66       Xaw Val Xaa Pro Xbx                                                - 67       Xby Vai Xaa Pro Xab                                                - 68       Xbz Val Xaa Pro Xab                                                - 69       Xca Val Xaa Pro Xab isomer 1                                       - 70       Xca Val Xaa Pro Xab isomer 2                                       - 71       Xbo Val Xaa Pro Xbx isomer 1                                       - 72       Xbo Val Xaa Pro Xbx isomer 2                                       - 73       Xau Val Xaa Pro Xbp                                                - 74       Xau Val Xaa Pro Xbx                                                - 75       Xbi Val Xaa Pro Xbx isomer 2                                       - 76       Xau Val Xaa Pro Xab isomer 1                                       - 77       Xau Val Xaa Pro Xab isomer 2                                       - 78       Xau Val Xaa Pro Xcb                                                - 79       Xbi Val Xaa Pro Xcb isomer 1                                       - 80       Xbi Val Xaa Pro Xcb isomer 2                                       - 81       Xbi Val Xaa Pro Xcc isomer 1                                       - 82       Xbi Val Xaa Pro Xcc isomer 2                                       - 83       Xbi Val Xaa Pro Xcd                                                - 84       Xbk Val Xaa Pro Xcc isomer 1                                       - 85       Xbk Val Xaa Pro Xcc isomer 2                                       - 86       Xax Val Xaa Pro Xbp isomer 1                                       - 87       Xax Val Xaa Pro Xbp isomer 2                                       - 88       Xbk Val Xaa Pro Xcb isomer 1                                       - 89       Xbk Val Xaa Pro Xcb isomer 2                                       - 90       Xau Val Xaa Pro Xcc                                                - 91       Xau Val Xaa Pro Xcd                                                - 92       Xba Val Xaa Pro Xcb isomer 1                                       - 93       Xba Val Xaa Pro Xcb isomer 2                                       - 94       Xbo Val Xaa Pro Xbp isomer 1                                       - 95       Xbo Val Xaa Pro Xbp isomer 2                                       - 96       Xau Val Xaa Pro Xbp isomer 1                                       - 97       Xau Val Xaa Pro Xbp isomer 2                                       - 98       Xbi Val Xaa Pro Xcd isomer 2                                       - 99       Xbk Val Xaa Pro Xcd                                                - 100      Xba Val Xaa Pro Xbp isomer 1                                       - 101      Xba Val Xaa Pro Xbp isomer 2                                       - 102      Xba Val Xaa Pro Xcc isomer 1                                       - 103      Xba Val Xaa Pro Xcc isomer 2                                       - 104      Xba Val Xaa Pro Xcd                                                - 105      Xce Val Xaa Pro Xab                                                - 106      Xcf Val Xaa Pro Xab                                                - 107      Xcg Val Xaa Pro Xab isomer 1                                       - 108      Xcg Val Xaa Pro Xab isomer 2                                       - 109      Xaw Val Xaa Pro Xch                                                - 110      Xaw Val Xaa Pro Xci                                                - 111      Xaw Val Xaa Pro Xck                                                - 112      Xaw Val Xaa Pro Xcl                                                - 113      Xaw Val Xaa Pro Xcm                                                - 114      Xaw Val Xaa Pro Xcn                                                - 115      Xaw Val Xaa Pro Xco                                                - 116      Xaw Val Xaa Pro Xcp                                                - 117      Xaw Val Xaa Pro Xcq                                                - 118      Xaw Val Xaa Pro Xcr                                                - 119      Xad Val Xaa Pro Xch                                                - 120      Xad Val Xaa Prb Xci                                                - 121      Xad Val Xaa Pro Xck                                                - 122      Xad Val Xaa Pro Xcl                                                - 123      Xad Val Xaa Pro Xcm                                                - 124      Xad Val Xaa Pro Xcn                                                - 125      Xad Val Xaa Pro Xco                                                - 126      Xad Val Xaa Pro Xcp                                                - 127      Xad Val Xaa Pro Xcq                                                - 128      Xad Val Xaa Pro Xcr                                                - 129      Xad Val Xaa Pro Xbx                                                - 130      Xau Val Xaa Pro Xch                                                - 131      Xau Val Xaa Pro Xci                                                - 132      Xau Val Xaa Pro Xck                                                - 133      Xau Val Xaa Pro Xcl                                                - 134      Xau Va1 Xaa Pro Xcm                                                - 135      Xau Val Xaa Pro Xcn                                                - 136      Xau Val Xaa Pro Xco                                                - 137      Xau Val Xaa Pro Xcp                                                - 138      Xau Val Xaa Pro Xcq                                                - 139      Xau Val Xaa Pro Xcr                                                - 140      Xau Val Xaa Pro Xbr                                                - 141      Xad Val Xaa Xal Xbx                                                - 142      Xau Val Xaa Xal Xbx                                                - 143      Xaw Val Xaa Xal Xbx                                                - 144      Xad Val Xaa Xal Xch                                                - 145      Xau Val Xaa Xal Xch                                                - 146      Xaw Val Xaa Xal Xch                                                - 147      Xad Val Xaa Xal Xcr                                                - 148      Xau Val Xaa Xal Xcr                                                - 149      Xaw Val Xaa Xal Xcr                                                - 150      Xad Val Xaa Xan Xbx                                                - 151      Xau Val Xaa Xan Xbx                                                - 152      Xaw Val Xaa Xan Xbx                                                - 153      Xad Val Xaa Xan Xch                                                - 154      Xau Val Xaa Xan Xch                                                - 155      Xaw Val Xaa Xan Xch                                                - 156      Xad Val Xaa Xan Xcr                                                - 157      Xau Val Xaa Xan Xar                                                - 158      Xaw Val Xaa Xan Xcr                                                - 159      Xau Ile Xaa Pro Xbx                                                - 160      Xad Ile Xaa Pro Xbx                                                - 161      Xaw Ile Xaa Pro Xch                                                - 162      Xad Ile Xaa Pro Xch                                                - 163      Xau Ile Xaa Pro Xah                                                - 164      Xaw Xcs Xaa Pro Xch                                                - 165      Xad Xcs Xaa Pro Xch                                                - 166      Xau Xcs Xaa Pro Xch                                                - 167      Xaw Xcs Xaa Pro Xbx                                                - 168      Xad Xcs Xaa Pro Xbx                                                - 169      Xau Xcs Xaa Pro Xbx                                                - 170      Xaw Val Xct Pro Xch                                                - 171      Xad Val Xct Pro Xch                                                - 172      Xau Val Xct Pro Xch                                                - 173      Xaw Val Xct Pro Xbx                                                - 174      Xad Val Xct Pro Xbx                                                - 175      Xau Val Xct Pro Xbx                                             ______________________________________                                    

The symbols Xaa in Table 1 represent the following amino acids orresidues thereof:

    ______________________________________                                        Xaa: N-methyl-valine                                                            Xab: Prolyl N-benzylamide                                                     Xac: L-N-methyl-piperidine-2-carboxylic acid                                  Xad: D-N-methyl-piperidine-2-carboxylic acid                                  Xae: N-methyl-L-proline                                                       Xaf: N-methyl-L-thiazolidine-4-carboxylic acid                                Xag: N,N-dimethylglycine                                                      Xah: L-proline                                                                Xai: L-piperidine-2-carboxylic acid                                           Xak: 2-[N,N-dimethylamino]-isobutyric acid                                    Xal: L-thiazolidine-4-carboxylic acid                                         Xam: N-propyl-D-piperidine-2-carboxylic acid                                  Xan: L-3,4-didehydroproline                                                   Xao: D-piperidine-2-carboxylic acid                                           Xap: proline tert.butylester                                                  Xaq: N-ethyl-D-piperidine-2-carboxylic acid                                   Xar: N-methyl-[2,2,5,5-tetramethyl]-L-thiazolidine-2-carboxylic acid              Xas: N-isopropyl-D-piperidine-2-carboxylic acid                           Xat: N,N-dimethyl-2-cyclopropyl-glycine                                       Xau: N,N-dimethyl-2-ethyl-2-phenyl-glycine                                    Xav: D-proline                                                                Xaw: N-methyl-D-proline                                                       Xax: N,N-dimethyl-2-[2-fluoro]phenyl-glycine                                  Xay: 1-aza-[3,3,0]bicyclooctyl-5-carboxylic acid                              Xaz: N,N-dimethyl-2-[4-fluoro]phenyl-glycine                                  Xba: N-methyl-[2,2,5,5-tetramethyl]-thiazolidine-2-carboxylic acid                Xbb: 2-(R,S)-ethyl-2-phenyl-glycine                                       Xbc: D,L-1-aminoindane-1-carboxylic acid                                      Xbd: N,N-dimethyl-2-(R,S)-methyl-2-phenyl-glycine                             Xbe: 2-[N,N-dimethylamino]indane-2-carboxylic acid                            Xbf: 5-[N,N-dimethylamino]-5,6,7,8-tetrahydronaphthalene-5-                    carboxylic acid                                                              Xbg: N-isopropyl-2-(R,S)-ethyl-2-phenyl-glycine                               Xbh: 1-[N,N-dimethylamino]indane-2-carboxylic acid                            Xbi: N,N-dimethyl-2-propyl-2-phenyl-glycine                                   Xbk: N,N-dimethyl-2-[4-methoxy]phenyl-glycine                                 Xbl: N-methyl-3-hydroxy-D,L-valine                                            Xbm: N,N-dimethyl-D,L-2-isopropyl-2-phenyl-glycine                            Xbn: proline-N-methoxy-N-methyl-amide                                         Xbo: N-methyl-piperidine-2-carboxylic acid                                    Xbp: proline-isopropylamide                                                   Xbq: proline-isoxazolidinyl                                                   Xbr: proline-N-methoxy-N-benzylamide                                          Xbs: N-methyl-D,L-proline                                                     Xbt: proline-[5-phenyl]isoxazolidinyl                                         Xbu: N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid                Xbv: N-methyl-azetidine-2-carboxylic acid                                     Xbw: N-isopropyl-azetidine-2-carboxylic acid                                  Xbx: proline-tert-butylamide                                                  Xby: N,N-dimethyl-[O-methyl]serine                                            Xbz: N,N-dimethyl-[O-methyl]threonine                                         Xca: N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid                Xcb: proline-pentyl (3) amide                                                 Xcc: proline-(R)-phenethylamide                                               Xcd: proline-(S)-phenethylamide                                               Xce: 1-[N,N-dimethylamino]cyclohexyl-1-carboxylic acid                        Xcf: 1-[N,N-dimethylamino]cyclopentyl-1-carboxylic acid                       Xcg: 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid                          - Xch:                                                                            #STR27##                                                                  - Xci:                                                                            #STR28##                                                                  - Xck:                                                                            #STR29##                                                                  - Xcl:                                                                            #STR30##                                                                  - Xcm:                                                                            #STR31##                                                                  - Xcn:                                                                            #STR32##                                                                  - Xco:                                                                            #STR33##                                                                  - Xcp:                                                                            #STR34##                                                                  - Xcq:                                                                            #STR35##                                                                  - Xcr:                                                                            #STR36##                                                                  - Xcs: L-2-tert-butyl-glycine                                                Xct: N-methyl-L-Isoleucine                                                  ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Results of FAB-MS analysis of selected compounds                                      Compound  Mol. weight                                                   No. measured                                                                ______________________________________                                         1            639                                                                2 639                                                                         3 627                                                                         4 703                                                                         5 625                                                                         6 611                                                                         7 625                                                                         8 625                                                                        10 667                                                                        12 625                                                                        13 606                                                                        14 653                                                                        15 699                                                                        16 667                                                                        17 639                                                                        18 639                                                                        19 643                                                                        20 611                                                                        21 599                                                                        22 693                                                                        23 693                                                                        24 651                                                                        25 693                                                                        26 693                                                                        27 699                                                                        28 675                                                                        29 673                                                                        30 689                                                                        31 689                                                                        32 701                                                                        33 701                                                                        34 715                                                                        35 717                                                                        36 701                                                                        37 701                                                                        38 717                                                                        39 717                                                                        40 705                                                                        41 705                                                                        42 643                                                                        43 715                                                                        44 703                                                                        45 579                                                                        46 593                                                                        47 593                                                                        48 577                                                                        49 591                                                                        50 591                                                                        51 591                                                                        52 655                                                                        53 667                                                                        54 657                                                                        55 657                                                                        56 687                                                                        57 611                                                                        58 639                                                                        59 639                                                                        60 667                                                                        61 687                                                                        62 669                                                                        63 669                                                                        64 605                                                                        65 605                                                                        66 591                                                                        67 643                                                                        68 657                                                                        69 687                                                                        70 687                                                                        71 605                                                                        72 605                                                                        73 655                                                                        74 669                                                                        75 683                                                                        76 703                                                                        77 703                                                                        78 683                                                                        79 697                                                                        80 697                                                                        81 731                                                                        82 731                                                                        83 731                                                                        84 719                                                                        85 719                                                                        86 645                                                                        87 645                                                                        88 685                                                                        89 685                                                                        90 717                                                                        91 717                                                                        92 679                                                                        93 679                                                                        94 591                                                                        95 591                                                                        96 655                                                                        97 655                                                                        98 731                                                                        99 719                                                                        100  651                                                                      101  651                                                                      102  713                                                                      103  713                                                                      104  713                                                                      105  666                                                                      106  653                                                                      107  687                                                                      108  687                                                                    ______________________________________                                    

Example 5

Evaluation of Biological Activity

In vitro Methodology

Cytotoxicity was measured using a standard methodology for adherent celllines, such as the microculture tetrazolium assay (MTT). Details of thisassay have been published (Alley, M. C. et al., Cancer Research 48:589-601, (1988)). Exponentially growing cultures of HT-29 coloncarcinoma cells were used to make microtiter plate cultures. Cells wereseeded at 5000-20,000 cells per well in 96-well plates (in 150 mL ofmedia), and grown overnight at 37° C. Test compounds were added, in10-fold dilutions varying from 10⁻⁴ M to 10⁻¹⁰ M. Cells were thenincubated for 48 hours. To determine the number of viable cells in eachwell, the MTT dye was added (50 mL of a 3 mg/mL solution of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline).This mixture was incubated at 37° C. for 5 hours, and then 50 mL of 25%SDS, pH 2, was added to each well. After an overnight incubation, theabsorbance of each well at 550 nm was read using an ELISA reader. Thevalues for the mean +/-SD of data from replicated wells were calculated,using the formula % T/C (% viable cells treated/control). Theconcentration of test compound which gives a T/C of 50% growthinhibition was designated as the IC₅₀.

Table 3 presents the IC₅₀ values determined in the HT-29 assay for aseries of compounds of the invention.

                  TABLE 3                                                         ______________________________________                                        Compound                                                                        No. HT-29 [IC.sub.50 ]                                                      ______________________________________                                         1            4.7 × 10.sup.-6                                              2 .sup. 6.8 × 10.sup.-10                                                3 3.5 × 10.sup.-8                                                       4 1.2 × 10.sup.-9                                                       5 5.0 × 10.sup.-9                                                       8 5.1 × 10.sup.-7                                                      10 1.3 × 10.sup.-7                                                      12 3.7 × 10.sup.-7                                                      13 1.0 × 10.sup.-9                                                      14 1.5 × 10.sup.-9                                                      15 1.7 × 10.sup.-7                                                      16 .sup. 7.3 × 10.sup.-10                                               17 6.3 × 10.sup.-8                                                      18 8.8 × 10.sup.-9                                                      22 6.4 × 10.sup.-7                                                      24 2.8 × 10.sup.-8                                                      27 3.7 × 10.sup.-8                                                      28 4.9 × 10.sup.-8                                                      29 3.6 × 10.sup.-8                                                      30 6.1 × 10.sup.-9                                                      31 2.0 × 10.sup.-7                                                      32 8.5 × 10.sup.-7                                                      33 1.2 × 10.sup.-6                                                      34 5.0 × 10.sup.-9                                                      35 1.4 × 10.sup.-7                                                      36 6.2 × 10.sup.-9                                                      37 1.9 × 10.sup.-7                                                      38 7.3 × 10.sup.-7                                                      39 2.5 × 10.sup.-8                                                      40 5.6 × 10.sup.-7                                                      41 7.3 × 10.sup.-6                                                      42 3.4 × 10.sup.-7                                                      43 5.9 × 10.sup.-8                                                      44 4.8 × 10.sup.-8                                                      45 5.6 × 10.sup.-8                                                      46 7.2 × 10.sup.-7                                                      47 2.3 × 10.sup.-8                                                      48 2.5 × 10.sup.-8                                                      49 8.8 × 10.sup.-8                                                      50 8.9 × 10.sup.-8                                                      51 4.6 × 10.sup.-8                                                      52 3.4 × 10.sup.-7                                                      53 5.0 × 10.sup.-9                                                      54 4.2 × 10.sup.-9                                                      55 5.6 × 10.sup.-8                                                      57 2.5 × 10.sup.-8                                                      58 6.3 × 10.sup.-8                                                      59 1.9 × 10.sup.-7                                                      60 1.8 × 10.sup.-9                                                      62 9.9 × 10.sup.-8                                                      63 5.6 × 10.sup.-8                                                      64 1.7 × 10.sup.-6                                                      65 9.7 × 10.sup.-8                                                      66 3.4 × 10.sup.-7                                                      67 3.4 × 10.sup.-7                                                      68 4.2 × 10.sup.-7                                                      70 7.1 × 10.sup.-6                                                      72 1.2 × 10.sup.-7                                                      73 1.4 × 10.sup.-9                                                      74 5.1 × 10.sup.-8                                                      75 8.5 × 10.sup.-7                                                      76 .sup. 2.3 × 10.sup.-10                                               77 7.2 × 10.sup.-9                                                      78 4.3 × 10.sup.-9                                                      79 1.7 × 10.sup.-6                                                      80 6.7 × 10.sup.-8                                                      81 1.3 × 10.sup.-7                                                      82 1.1 × 10.sup.-8                                                      83 1.3 × 10.sup.-7                                                      84 1.2 × 10.sup.-6                                                      85 9.5 × 10.sup.-6                                                      90 .sup. 9.3 × 10.sup.-10                                               91 .sup. 8.3 × 10.sup.-10                                               92 1.5 × 10.sup.-6                                                      93 1.8 × 10.sup.-6                                                      94 3.0 × 10.sup.-6                                                      95 1.1 × 10.sup.-8                                                      96 1.7 × 10.sup.-9                                                      97 3.2 × 10.sup.-8                                                      98 6.0 × 10.sup.-9                                                      99 3.8 × 10.sup.-6                                                      100  2.3 × 10.sup.-6                                                    101  2.1 × 10.sup.-6                                                    102  1.2 × 10.sup.-7                                                    103  1.1 × 10.sup.-7                                                    104  3.5 × 10.sup.-6                                                    105  1.8 × 10.sup.-8                                                    106  9.7 × 10.sup.-8                                                    108  7.1 × 10.sup.-6                                                  ______________________________________                                    

In vivo Methodology

Compounds of this invention may be further tested in any of the variouspreclinical assays for in vivo activity which are indicative of clinicalutility. Such assays are conducted with nude mice into which tumortissue, preferably of human origin, has been transplanted("xenografted"), as is well known in this field. Test compounds areevaluated for their anti-tumor efficacy following administration to thexenograft-bearing mice.

More specifically, human tumors grown in athymic nude mice can betransplanted into new recipient animals, using tumor fragments which areabout 50 mg in size. The day of transplantation is designated as day 0.Six to ten days later, the mice are treated with the test compoundsgiven as an intravenous or intraperitoneal injection, in groups of 5-10mice at each dose. Compounds are given daily for 5 days, 10 days or 15days, at doses from 10-100 mg/kg body weight. Tumor diameters and bodyweights are measured twice weekly. Tumor masses are calculated using thediameters measured with Vernier calipers, and the formula:

    (length×width.sup.2)/2=mg of tumor weight

Mean tumor weights are then calculated for each treatment group, and T/Cvalues are determined for each group relative to the untreated controltumors.

Equivalents

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed in the scope of the following claims.

We claim:
 1. A compound of the formula

    A-B-D-E-F-(G).sub.r -(K).sub.s -L,

wherein r and s are each independently, 0 or 1; A is a prolinederivative of Formula II_(a), ##STR37## wherein n_(a) is 0 to 3; R_(a)is hydrogen, or unsubstituted or fluorine-substituted normal, branchedor cyclic C₁ -C₃ -alkyl; R¹ _(a) is hydrogen, C₁ -C₃ -alkyl, phenyl, orsubstituted phenyl; or R_(a) and R¹ _(a) together form a propylenebridge; and R² _(a), R³ _(a), R⁴ _(a) and R⁵ _(a) are each,independently, hydrogen or alkyl; or an α-amino acid derivative ofFormula III_(a), ##STR38## wherein R_(a) is hydrogen or unsubstituted orfluorine-substituted C₁ -C₃ -alkyl; R¹ _(a) or C₁ -C₄ -alkyl; R⁶ _(a) isalkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl; or R¹_(a) is an alkyl group and R⁶ _(a) is C₁ -C₆ -alkyl, cycloalkylmethyl,benzyl or substituted benzyl; and R⁷ _(a) is hydrogen or alkyl; or anα-amino acid derivative of Formula IV_(a), ##STR39## wherein m_(a) is 1or 2; R⁷ _(a) is hydrogen or alkyl; R_(a) is hydrogen, or unsubstitutedor fluorine-substituted alkyl; or an α-amino acid derivative of FormulaV_(a), ##STR40## wherein R⁷ _(a) is hydrogen or alkyl and R_(a) ishydrogen, or unsubstituted or fluorine-substituted alkyl; or an α-aminoacid of Formula VI_(a), ##STR41## wherein R_(a) is hydrogen, orunsubstituted or fluorine-substituted alkyl; R¹ _(a) hydrogen, alkyl,phenyl, or substituted phenyl; or R_(a) and R¹ _(a) together form apropylene bridge; and X_(a) is hydroxy, alkoxy or fluorine; or anα-amino acid of Formula VII_(a), ##STR42## wherein R_(a) is hydrogen, orunsubstituted or fluorine-substituted alkyl; R¹ _(a) is hydrogen, alkyl,phenyl, or substituted phenyl; or R_(a) and R¹ _(a) together form apropylene bridge; and R² _(a), R³ _(a), R⁴ _(a) and R⁵ _(a) are each,independently, hydrogen or alkyl; or an α-amino acid residue of FormulaVIII_(a), ##STR43## wherein R_(a) is hydrogen, or unsubstituted orfluorine-substituted alkyl; or a 2-azabicyclo[2.2.1]heptane-3-carboxylicacid derivative of Formula IX_(a), ##STR44## wherein the 3-carbonylmoiety is in the endo or exo position, Z_(a) is a single bond or adouble bond, and R_(a) is hydrogen or unsubstituted orfluorine-substituted alkyl; or an α-amino acid residue of Formula X_(a),##STR45## wherein n_(a) is 1, 2 or 3, and R⁷ _(a) is hydrogen or alkyland R_(a) is hydrogen, unsubstituted alkyl or fluorine-substitutedalkyl; B is a valyl, isoleucyl, allo-isoleucyl, norvalyl,2-tert-butylglycyl or 2-ethylglycyl residue; or an α-amino acid residueof Formula II_(b), ##STR46## wherein R¹ _(b) is hydrogen, and R² _(b) isalkyl or alkenyl; or R¹ _(b) and R² _(b) together form an isopropylidenegroup; D is an N-alkylvalyl, N-alkyl-2-ethylglycyl,N-alkyl-2-tert-butylglycyl, N-alkylnorleucyl, N-alkylisoleucyl,N-alkyl-allo-isoleucyl or N-alkylnorvalyl residue; or an α-amino acidresidue of Formula II_(d), ##STR47## wherein R_(d) is hydrogen, orunsubstituted or fluorine-substituted alkyl; R¹ _(d) is hydrogen; and R²_(d) is alkyl, substituted alkyl or alkenyl; or R¹ _(d) and R² _(d)together form an isopropylidene group; or an α-amino acid residue ofFormula III_(d), ##STR48## wherein n_(d) is 1 or 2; R³ _(d) is hydrogen,alkyl or fluorine-substituted alkyl; and X_(d) is hydrogen; or n_(d) is1 and X_(d) is fluorine, hydroxy, methoxy, or ethoxy; E is a prolyl,thiazolidinyl-4-carbonyl, homoprolyl,or hydroxyprolyl residue; or anα-amino acid residue of Formula II_(e), ##STR49## wherein n_(e) is 0, 1or 2, R¹ _(e) is hydrogen, or unsubstituted or fluorine-substitutedalkyl; R² _(e) and R³ _(e) are each, independently, hydrogen or alkyl;R⁴ _(e) is hydrogen, hydroxy or alkoxy; and R⁵ _(e) is hydrogen orfluorine; or n, is 1 and R³ _(e) and R⁴ _(e) together form a doublebond; or n_(e) is 1 and R⁴ _(e) and R⁵ _(e) together form adouble-bonded oxygen diradical; or n_(e) is 1 or 2 and R¹ _(e) and R²_(e) together form a double bond; or an aminocyclopentanecarboxylic acidresidue of Formula III_(e), ##STR50## wherein R_(e) is alkyl and R¹ _(e)is hydrogen, or unsubstituted or fluorine-substituted alkyl; F is aprolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolyl residue;or an α-amino acid residue of Formula II_(f), ##STR51## wherein n_(f) is0, 1 or 2, R¹ _(f) is hydrogen, or unsubstituted or fluorine-substitutedalkyl; R² _(f) and R³ _(f) are each, independently, hydrogen or methyl;R⁴ _(f) is hydrogen, hydroxy, alkoxy, or fluorine; R⁵ _(f) is hydrogenor fluorine; or n_(f) is 1 and R³ _(f) and R⁴ _(f) together form adouble bond; or n_(f) is 1 and R⁴ _(f) and R⁵ _(f) together form adouble-bonded oxygen diradical; or n_(f) is 1 or 2 and R¹ _(f) and R²_(f) together form a double bond; or a 2- or3-aminocyclopentanecarboxylic acid residue of Formula III_(f), ##STR52##wherein R_(f) is alkyl and R¹ _(f) is hydrogen, or unsubstituted orfluorine-substituted alkyl; or an N-alkylglycyl or N-alkylalanylresidue; G is an α-amino acid residue of Formula II_(g), ##STR53##wherein R¹ _(g) is hydrogen or alkyl and R² _(g) is hydrogen, alkyl,arylalkyl, heteroarylalkyl, phenyl or substituted phenyl; or R¹ _(g) andR² _(g), together with the α-carbon atom, form a C₅ -C₆ ring or abenzo-fused C₅ ring; K is an α-amino acid of Formula II_(k), ##STR54##wherein R¹ _(k) is hydrogen, or alkyl; and R² _(k) is hydrogen, alkyl,arylalkyl, heteroarylalkyl, phenyl or substituted phenyl; or R¹ _(g) andR² _(g), together with the α-carbon atom, form a cyclopentane ring or abenzo-fused cyclopentane ring; and L is a substituted or unsubstitutedamino, hydrazido, aminoxy or oximato group.
 2. The compound of claim 1wherein A is a proline derivative of Formula II_(a) ; R_(a) is hydrogen,methyl, ethyl, normal propyl, isopropyl, cyclopropyl, 2-fluoroethyl,2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl,1-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluoroethyl; R¹ _(a) ishydrogen, methyl, ethyl, propyl, phenyl, or substituted phenyl, whereinthe phenyl substituents comprise one or more alkyl, alkoxy,trifluoromethyl or nitro groups; or R_(a) and R¹ _(a) together form apropylene bridge; and R² _(a), R³ _(a), R⁴ _(a) and R⁵ _(a) are each,independently, hydrogen or methyl.
 3. The compound of claim 1 wherein Ais an α-amino acid residue of Formula III_(a), wherein R_(a) ishydrogen, methyl, ethyl, normal propyl, isopropyl, cyclopropyl,2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl,1-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluoroethyl; R¹ _(a) is a C₁-C₃ -alkyl group; R⁶ _(a) is methoxymethyl, 1-methoxyethyl, vinyl,1-methylvinyl, 1-trifluoromethylvinyl, 1-trifluoromethylethyl,1-trifluoromethyl-2,2,2-trifluoroethyl, 1,1-dimethylhydroxymethyl,phenyl or substituted phenyl, wherein the phenyl substituents compriseone or more halogen atoms or one or more C₁ -C₄ -alkyl, methoxy,trifluoromethyl or nitro groups; or R¹ _(a) is C₁ -C₃ -alkyl and R⁶ _(a)is C₁ -C₆ -alkyl, cycloalkylmethyl, benzyl or substituted benzyl,wherein the benzyl substituents comprise one or more halogen atoms, orone or more C₁ -C₄ -alkyl, methoxy, ethoxy, trifluoromethyl or nitrogroups; and R⁷ _(a) is methyl, ethyl or isopropyl.
 4. The compound ofclaim 1 wherein A is an α-amino acid residue of Formula IV_(a), whereinR⁷ _(a) is methyl, ethyl or isopropyl; and R_(a) is hydrogen, methyl,ethyl, n-propyl, isopropyl, cyclopropyl, 2-fluoroethyl,2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl,1-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluoroethyl.
 5. The compoundof claim 1 wherein A is an α-amino acid residue of Formula V_(a),wherein R⁷ _(a) is methyl, ethyl or isopropyl and R_(a) is hydrogen,methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-fluoroethyl,2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl,1-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluoroethyl.
 6. The compoundof claim 1 wherein A is an α-amino acid residue of Formula VI_(a),wherein R_(a) is hydrogen, methyl, ethyl, normal propyl, isopropyl,cyclopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,1-methyl-2-fluoroethyl, 1-fluoromethyl-2-fluoroethyl, or1-methyl-2-fluoroethyl; R¹ _(a) is hydrogen, methyl, ethyl, propyl,phenyl, or substituted phenyl, wherein the phenyl substituents compriseone or more alkyl, alkoxy, trifluoromethyl or nitro groups; or R_(a) andR¹ _(a) together form a propylene bridge; and X_(a) is a hydroxy,methoxy, or ethoxy group, or a fluorine atom.
 7. The compound of claim 1wherein A is an α-amino acid residue of Formula VII_(a), wherein R_(a)is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl,1-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluoroethyl; R¹ _(a) ishydrogen, methyl, ethyl, propyl, phenyl, or substituted phenyl, whereinthe phenyl substituents comprise one or more alkyl, alkoxy,trifluoromethyl or nitro groups; or R_(a) and R¹ _(a) together form apropylene bridge; and R² _(a), R³ _(a), R⁴ _(a) and R⁵ _(a) are each,independently, hydrogen or methyl.
 8. The compound of claim 1 wherein Ais an α-amino acid residue of Formula VIII_(a), wherein R_(a) ishydrogen, methyl, ethyl, normal propyl, isopropyl, cyclopropyl,2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl,1-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluoroethyl.
 9. The compoundof claim 1 wherein A is an amino acid residue of Formula IX_(a), whereinR_(a) is hydrogen, methyl, ethyl, normal propyl, isopropyl, cyclopropyl,2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl,1-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluoroethyl.
 10. Thecompound of claim 1 wherein A is an α-amino acid residue of FormulaX_(a), wherein R⁷ _(a) is methyl, ethyl or isopropyl and R_(a) ishydrogen, methyl, ethyl, normal propyl, isopropyl, cyclopropyl,2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl,1-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluoroethyl.
 11. Thecompound of claim 1 wherein B is a residue of Formula II_(b), wherein R¹_(b) is hydrogen and R² _(b) is cyclopropyl, n-butyl, isobutyl, tertiarybutyl, methoxymethyl, 1-methoxyethyl, or 1-methylvinyl.
 12. The compoundof claim 1 wherein D is an N-alkylvalyl residue, anN-alkyl-2-ethylglycyl residue, an N-alkyl-2-tert-butylglycyl residue, anN-alkylnorleucyl residue, an N-alkylisoleucyl residue, anN-alkyl-allo-isoleucyl residue or an N-alkylnorvalyl residue, whereinthe N-alkyl group is methyl or ethyl.
 13. The compound of claim 1wherein D is an α-amino acid residue of Formula II_(d), R¹ _(d) ishydrogen and R² _(d) is cyclopropyl, methoxymethyl, 1-methoxyethyl, or1-methylvinyl.
 14. The compound of claim 1 wherein D is an α-amino acidresidue of Formula III_(d), wherein R³ _(d) is hydrogen, methyl, ethyl,normal propyl, isopropyl, cyclopropyl, 2-fluoroethyl,2,2,2,-trifluoroethyl, 1-methyl-2-fluoroethyl, or1-fluoromethyl-2-fluoroethyl; and X_(d) is a hydrogen atom; or n_(d) is1 and X_(d) is a fluorine atom, or a hydroxy, methoxy, or ethoxy group.15. The compound of claim 1 wherein E is an α-amino acid residue ofFormula II_(e), and R¹ _(e) is hydrogen, methyl, ethyl, n-propyl,isopropyl, cyclopropyl, 2-fluoroethyl, 2,2,2,-trifluoroethyl,1-methyl-2-fluoroethyl, or 1-fluoromethyl-2-fluoroethyl; R² _(e) and R³_(e) are each, independently, hydrogen or methyl; R⁴ _(e) is a hydrogenatom or a hydroxy, methoxy or ethoxy group; and R⁵ _(e) is hydrogen orfluorine; or n_(e) is 1 and R³ _(e) and R⁴ _(e) together form a doublebond; or n_(e) is 1 and R⁴ _(e) and R⁵ _(e) together form adouble-bonded oxygen diradical; or n_(e) is 1 or 2 and R¹ _(e) and R²_(e) together form a double bond.
 16. The compound of claim 1 wherein Eis an aminocyclopentanecarboxylic acid residue of Formula III_(e),wherein R_(e) is methyl or ethyl group and R¹ _(e) is hydrogen, ormethyl, ethyl, normal propyl, isopropyl, cyclopropyl, 2-fluoroethyl,2,2,2,-trifluoroethyl, 1-methyl-2-fluoroethyl, or1-fluoromethyl-2-fluoroethyl.
 17. The compound of claim 1 wherein F isan α-amino acid residue of Formula II_(f), wherein R¹ _(f) is a hydrogenatom, or methyl, ethyl, normal propyl, isopropyl, cyclopropyl,2-fluoroethyl, 2,2,2,-trifluoroethyl, 1-methyl-2-fluoroethyl, or1-fluoromethyl-2-fluoroethyl; R² _(f) is a hydrogen atom or a methylgroup; R³ _(f) is a hydrogen atom or a methyl group; R⁴ _(f) is ahydrogen atom, a hydroxy, methoxy, ethoxy, or a fluorine atom; R⁵ _(f)is a hydrogen atom or a fluorine atom; or n_(f) is 1 and R³ _(f) and R⁴_(f) together form a double bond; or n_(f) is 1 and R⁴ _(f) and R⁵ _(f)together form a double-bonded oxygen radical; or n_(f) is 1 or 2 and R¹_(f) and R² _(f) together form a double bond.
 18. The compound of claim1 wherein F is a 2- or 3-aminocyclopentanecarboxylic acid residue ofFormula III_(f), wherein R_(f) is methyl or ethyl and R¹ _(f) ishydrogen, methyl, ethyl, normal propyl, isopropyl, cyclopropyl,2-fluoroethyl, 2,2,2,-trifluoroethyl, 1-methyl-2-fluoroethyl, or1-fluoromethyl-2-fluoroethyl.
 19. The compound of claim 1 wherein F isan N-alkylglycyl residue or an N-alkylalanyl residue and the N-alkylgroup is methyl or ethyl.
 20. The compound of claim 1 wherein G is anα-amino acid residue of Formula II_(g), wherein R¹ _(g) is hydrogen,methyl, ethyl or n-propyl, and R² _(g) is hydrogen, ethyl, isopropyl,tert-butyl, isobutyl, 2-methylpropyl, cyclohexylmethyl, benzyl,thiazolyl-2-methyl, pyridyl-2-methyl, n-butyl, 2,2-dimethylpropyl,naphthylmethyl, n-propyl, phenyl or substituted phenyl, wherein thephenyl substituents are one or more halogen atoms, one or more C₁ -C₄-alkyl, methoxy, ethoxy, nitro or trifluoromethyl groups or adioxomethylene group.
 21. The compound of claim 1 wherein K is anα-amino acid of Formula II_(k), wherein R¹ _(k) is hydrogen, methyl,ethyl or normal propyl, and R² _(k) is hydrogen, ethyl, isopropyl,tert-butyl, isobutyl, 2-methylpropyl, cyclohexylmethyl, benzyl,thiazolyl-2-methyl, pyridyl-2-methyl, normal butyl, 2,2-dimethylpropyl,naphthylmethyl, n-propyl, phenyl or substituted phenyl, wherein thephenyl substituents comprise one or more halogen atoms, or one or moreC₁ -C₄ -alkyl, methoxy, ethoxy, nitro or trifluoromethyl groups or adioxomethylene group; or R¹ _(g) and R² _(g), together with the α-carbonatom, form a cyclopentane ring or a benzo-fused cyclopentane ring. 22.The compound of claim 1 wherein L is an amino group of Formula II_(l),##STR55## wherein R¹ _(l) is a hydrogen atom, a normal or branched,saturated or unsaturated C₁ -C₁₈ -alkoxy group, a substituted orunsubstituted aryloxy group, a substituted or unsubstituted aryl-C₁ -C₆-alkoxy group, a substituted or unsubstituted aryloxy-C₁ -C₆ -alkoxygroup, wherein the aryl substituents comprise one or more halogen atomsor one or more C₁ -C₄ -alkyl, methoxy, ethoxy, trifluoromethyl,dioxymethylene, or nitro groups; or a heteroaryl-C₁ -C₆ -alkoxy group;andR² _(l) is a hydrogen atom, a normal or branched C₁ -C₁₈ -alkylgroup, a normal or branched C₁ -C₁₈ alkenyl group, a C₃ -C₁₀ -cycloalkylgroup, an aryl group or a substituted aryl group, wherein the arylsubstituents comprise one or more halogen atoms, or one or more C₁ -C₄-alkyl, methoxy, ethoxy, trifluoromethyl, cyano or nitro groups, a C₁-C₇ -alkoxycarbonyl group, a dioxymethylene group, a C₁ -C₇-alkylsulfonyl group, an amino group or a C₁ -C₆ -dialkylamino group; aheteroaryl group or a substituted heteroaryl group derived fromimidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole,thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole,benzofuran, benzothiophene, indole, isoindole, indazole, quinoline,pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole,oxadiazole, thiadiazole or pyridine, wherein the heteroaryl substituentscomprise one or more C₁ -C₆ -alkyl, hydroxyl or phenyl groups.
 23. Thecompound of claim 22 wherein R² _(l) is of Formula II_(r), ##STR56##wherein a_(l) is 0, 1, 2, 3, 4, or 5; R³ _(l) is methyl, ethyl, normalpropyl or isopropyl; and R⁴ _(l) is a saturated or partially unsaturatedcarbocyclic system comprising from about 3 to about 10 carbon atoms, anaryl group or a substituted aryl group, wherein the aryl substituentscomprise one or more halogen atoms, or one or more C₁ -C₄ -alkyl groups,methoxy, ethoxy, trifluoromethyl, cyano or nitro groups, a C₁ -C₇-alkoxycarbonyl group, a dioxymethylene group, a C₁ -C₇ -alkylsulfonylgroup, an amino group or a C₁ -C₆ -dialkylamino group; a heteroarylgroup or a substituted heteroaryl group derived from imidazole,isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan,pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran,benzothiophene, indole, isoindole, indazole, quinoline, pyridazine,pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole,thiadiazole or pyridine, wherein the heteroaryl substituents compriseone or more C₁ -C₆ -alkyl, hydroxyl or phenyl groups.
 24. The compoundof claim 22 wherein R² _(l) is of Formula III_(r),

    --(CH.sub.2).sub.2 --W.sub.1 --R.sup.5.sub.l               (III.sub.r)

wherein W_(l) is an N(R⁶ _(l)) group, an oxygen atom or a sulfur atom;R⁵ _(l) and R⁶ _(l) are each, independently, a hydrogen atom or a C₁ -C₄-alkyl, C₃ -C₇ -cycloalkyl, aryl, arylmethyl, substituted aryl, orsubstituted arylmethyl group, wherein the aryl substituents comprise oneor more halogen atoms, or one or more C₁ -C₄ -alkyl groups, methoxy,ethoxy, trifluoromethyl, cyano or nitro groups, a C₁ -C₇ -alkoxycarbonylgroup, a dioxymethylene group, a C₁ -C₇ -alkylsulfonyl group, an aminogroup or a C₁ -C₆ -dialkylamino group; or R⁶ _(l) is a C₁ -C₁₈ -alkanoylgroup or a benzoyl group.
 25. The compound of claim 22 wherein R² _(l)is a monovalent radical of Formula IV_(r),

    --(CH.sub.2).sub.b.sbsb.l --Z.sub.l                        (IV.sub.r)

wherein b_(l) is 2, 3, or 4 and Z_(l) is a formyl, aminocarbonyl,hydrazinocarbonyl, cyclic acetal, cyclic thioacetal, acyclic acetal oracyclic thioacetal group.
 26. The compound of claim 22 wherein R² _(l)is of Formula V_(r), ##STR57## wherein b_(l) is 2, 3, or 4; andR⁷ _(l)is a polyglycol group of the formula --O--(CH₂ CH₂ O)_(d).spsb.l--CH₃,wherein d_(l) is between about 2 and about 4, or between about 40 andabout
 90. 27. The compound of claim 22 wherein R² _(l) is of FormulaVI_(r), ##STR58## and R⁸ _(l) is a hydrogen atom, or a C₁ -C₄ alkanoyl,C₁ -C₄ alkyl, benzoyl, or benzyl group.
 28. The compound of claim 1wherein L is a β-hydroxylamino group of Formula III_(l), ##STR59##wherein R⁹ _(l) is a hydrogen atom, or a C₁ -C₆ -alkyl, an aryl group ora substituted aryl group, wherein the aryl substituents comprise one ormore halogen atoms, or one or more C₁ -C₄ -alkyl groups, methoxy,ethoxy, trifluoromethyl, cyano or nitro groups, a C₁ -C₇ -alkoxycarbonylgroup, a dioxymethylene group, a C₁ -C₇ -alkylsulfonyl group, an aminogroup or a C₁ -C₆ -dialkylamino group; andR¹⁰ _(l) is a hydrogen atom, amethyl group or a phenyl group.
 29. The compound of claim 1 wherein atleast one of r and s is 1, and L is an amino group of Formula IV_(l),##STR60## wherein R² _(l) and R⁴ _(l) are each, independently, hydrogenor C₁ -C₁₀ -alkyl; or R² _(l), R⁴ _(l) and the α-carbon together form aC₅ -C₆ -carbocycle.
 30. The compound of claim 1 wherein L is a hydrazidogroup of Formula V_(l), ##STR61## wherein R¹² _(l) is a hydrogen atom, anormal or branched C₁ -C₈ -alkyl group, a C₃ -C₈ -cycloalkyl group, a C₃-C₈ -cycloalkyl-C₁ -C₄ -alkyl group, an aryl group, an aryl-C₁ -C₄-alkyl group, or a substituted aryl or aryl-C₁ -C₄ -alkyl group whereinthe aryl substituents comprise one or more halogen atoms, or one or moremethoxy, ethoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C₁ -C₇-alkoxycarbonyl, C₁ -C₇ -alkylsulfonyl, amino, or C₁ -C₇ -dialkylaminogroups; or a heteroaryl-C₁ -C₄ -alkyl group, wherein the heteroarylgroup is derived from imidazole, pyrrole, thiophene, furan, thiazole,oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole, thiadiazole,isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine,benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyran,indole, isoindole, indazole or quinoline and the heteroaryl substituentscomprise one or more C₁ -C₆ -alkyl, hydroxyl or phenyl groups; andR¹¹_(l) is a hydrogen atom; or r is 1, s is 1 or both r and s are 1, andR¹¹ _(l) is a normal or branched C₁ -C₈ -alkyl group, a C₃ -C₈-cycloalkyl group, a C₃ -C₈ -cycloalkyl-C₁ -C₄ -alkyl group, an aryl-C₁-C₄ -alkyl group, an aryl group or a substituted aryl-C₁ -C₄ -alkyl oraryl group, wherein the aryl substituents comprise one or more halogenatoms, or one or more C₁ -C₄ -alkyl groups, methoxy, ethoxy,trifluoromethyl, cyano or nitro groups, a C₁ -C₇ -alkoxycarbonyl group,a dioxymethylene group, a C₁ -C₇ -alkylsulfonyl group, an amino group ora C₁ -C₆ -dialkylamino group; a heteroaryl group a heteroaryl-C₁ -C₄-alkyl group or a substituted heteroaryl or heteroaryl-C₁ -C₄ -alkylgroup derived from imidazole, isoxazole, isothiazole, thiazole, oxazole,pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine,indole, benzofuran, benzothiophene, indole, isoindole, indazole,quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran,benzothiazole, oxadiazole, thiadiazole or pyridine, wherein theheteroaryl substituents comprise one or more C₁ -C₆ -alkyl, hydroxyl orphenyl groups; or R¹¹ _(l) and R¹² _(l) together form a propylene bridgeor a butylene bridge.
 31. The compound of claim 1 wherein L is amonovalent radical of the formula --W--R¹³ _(l), whereinW is oxygen orsulfur; R¹³ _(l) is a C₃ -C₁₀ -cycloalkyl, straight-chain or branched C₂-C₁₆ -alkenylmethyl, C₁ -C₁₆ -alkyl or halogen-substituted C₁ -C₁₆-alkyl group or R¹³ _(l) is a monovalent radical of the formula --(CH₂)₁e--R¹⁴ _(l), e is 1, 2, or 3, and R¹⁴ _(l) is a saturated or partiallyunsaturated C₃ -C₁₀ -carbocyclic group; or R¹³ _(l) is a monovalentradical of the formula --[CH₂ --CH═C(CH₃)--CH₂ ]_(f) --H, and f is 1, 2,3, or 4; or R¹³ _(l) is a monovalent radical of the formula --[CH₂ --CH₂--O]_(g) --CH₃, and g is 1, 2, 3, 4, or 5; or R¹³ _(l) is a monovalentradical of the formula --(CH₂)_(h) --X, wherein h is 0, 1, 2, or 3, X isan aryl group or a substituted aryl group, wherein the aryl substituentscomprise one or more halogen atoms, or one or more C₁ -C₄ -alkyl groups,methoxy, ethoxy, trifluoromethyl, cyano or nitro groups, a C₁ -C₇-alkoxycarbonyl group, a dioxymethylene group, a C₁ -C₇ -alkylsulfonylgroup, an amino group or a C₁ -C₆ -dialkylamino group; or X is aheteroaryl group or a substituted heteroaryl group derived fromimidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole,thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole,benzofuran, benzothiophene, indole, isoindole, indazole, quinoline,pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole,oxadiazole, thiadiazole or pyridine, wherein the heteroaryl substituentscomprise one or more C₁ -C₆ -alkyl, hydroxyl or phenyl groups, anaryl-C₁ -C₄ -alkyl group or a heteroaryl-C₁ -C₄ -alkyl group; or R¹³_(l) is a monovalent radical of the formula --(CH₂)_(b) --W_(l) --R⁵_(l), b is an integer, W_(l) is an oxygen atom, a sulfur atom, or an NR⁶_(l) group, b_(l) is 2, 3, or 4; R⁵ _(l) is a saturated or partiallyunsaturated carbocyclic system which contains from about 3 to about 10carbon atoms, an aryl or substituted aryl group, wherein the arylsubstituents comprise one or more halogen atoms, or one or more C₁ -C₄-alkyl groups, methoxy, ethoxy, trifluoromethyl, cyano or nitro groups,a C₁ -C₇ -alkoxycarbonyl group, a dioxymethylene group, a C₁ -C₇-alkylsulfonyl group, an amino group or a C₁ -C₆ -dialkylamino group; aheteroaryl group or a substituted heteroaryl group derived fromimidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole,thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole,benzofuran, benzothiophene, indole, isoindole, indazole, quinoline,pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole,oxadiazole, thiadiazole or pyridine, wherein the heteroaryl substituentscomprise one or more C₁ -C₆ -alkyl, hydroxyl or phenyl groups; R⁶ _(l)is a hydrogen atom, or a C₁ -C₄ -alkyl, C₃ -C₇ -cycloalkyl, C₁ -C₁₈-alkanoyl, benzoyl, aryl or arylmethyl group or a substituted aryl orarylmethyl group, wherein the aryl substituents comprise one or morehalogen atoms, or one or more C₁ -C₄ -alkyl groups, methoxy, ethoxy,trifluoromethyl, cyano or nitro groups, a C₁ -C₇ -alkoxycarbonyl group,a dioxymethylene group, a C₁ -C₇ -alkylsulfonyl group, an amino group ora C₁ -C₆ -dialkylamino group.
 32. The compound of claim 1 wherein L isan aminoxy group of the formula --O--N(R¹⁵ _(l))(R¹⁶ _(l)) wherein R¹⁵_(l) and R¹⁶ _(l) are each, independently, a hydrogen atom, a normal orbranched C₁ -C₈ -alkyl group, a halogen-substituted normal or branchedC₁ -C₈ -alkyl group, a C₃ -C₈ -cycloalkyl group, a C₃ -C₈ -cycloalkyl-C₁-C₄ alkyl group, an aryl group, an aryl-C₁ -C₄ -alkyl group or asubstituted aryl or aryl-C₁ -C₄ -alkyl group, wherein the arylsubstituents comprise one or more halogen atoms, or one or more C₁ -C₄-alkyl groups, methoxy, ethoxy, trifluoromethyl, cyano or nitro groups,a C₁ -C₇ -alkoxycarbonyl group, a dioxymethylene group, a C₁ -C₇-alkylsulfonyl group, an amino group or a C₁ -C₆ -dialkylamino group; aheteroaryl group, a heteroaryl-C₁ -C₄ -alkyl group or a substitutedheteroaryl or heteroaryl-C₁ -C₄ -alkyl group derived from imidazole,isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan,pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran,enzothiophene, indole, isoindole, indazole, quinoline, pyridazine,pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole,thiadiazole or pyridine, wherein the heteroaryl substituents compriseone or more C₁ -C₆ -alkyl, hydroxyl or phenyl groups; or R¹⁵ _(l) andR¹⁶ _(l) together with the nitrogen atom form a heterocyclic ringstructure comprising 5, 6, or 7 atoms.
 33. The compound of claim 1wherein L is a oximato group of the formula --O--N═C(R¹⁵ _(l))(R¹⁶_(l)), wherein R¹⁵ _(l) and R¹⁶ _(l) are each, independently, a hydrogenatom, a normal or branched C₁ -C₈ -alkyl group, a halogen-substitutednormal or branched C₁ -C₈ -alkyl group, a C₃ -C₈ -cycloalkyl group, a C₃-C₈ -cycloalkyl-C₁ -C₄ -alkyl group, an aryl group, an aryl-C₁ -C₄-alkyl group or a substituted aryl or aryl-C₁ -C₄ -alkyl group, whereinthe aryl substituents comprise one or more halogen atoms, or one or moreC₁ -C₄ -alkyl groups, methoxy, ethoxy, trifluoromethyl, cyano or nitrogroups, a C₁ -C₇ -alkoxycarbonyl group, a dioxymethylene group, a C₁ -C₇-alkylsulfonyl group, an amino group or a C₁ -C₆ -dialkylamino group; aheteroaryl group or a substituted heteroaryl group derived fromimidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole,thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole,benzofuran, benzothiophene, indole, isoindole, indazole, quinoline,pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole,oxadiazole, thiadiazole or pyridine, wherein the heteroaryl substituentscomprise one or more C₁ -C₆ -alkyl, hydroxyl or phenyl groups; or R¹⁵_(l) and R¹⁶ _(l), together with the carbon atom, form a cyclic systemor a cyclic system which is fused to an aromatic ring system.
 34. Thecompound of claim 33 wherein the cyclic system is selected from thegroup consisting of ##STR62##
 35. The compound of claim 1 wherein A isan amino acid derivative selected from the group consisting ofN-alkyl-D-prolyl, N-alkyl-L-prolyl, N-alkyl-D-piperidine-2-carbonyl,N-alkyl-L-piperidine-2-carbonyl, N,N-dialkyl-D-2-ethyl-2-phenylglycyland N,N-dialkyl-L-2-ethyl-2-phenylglycyl, wherein alkyl is methyl, ethylor isopropyl; andB is valyl, isoleucyl or 2-t-butyl-L-glycyl.
 36. Acompound of the formula

    A-B-D-E-F-L,

wherein A is an amino acid derivative selected from the group consistingof D-N-methyl-piperidine-2-carbonyl, L-N-methyl-piperidine-2-carbonyl,N,N-dimethylamino-isobutyryl, N-methyl-L-prolyl,N-methyl-L-thiazolidine-4-carbonyl, N,N-dimethylglycyl, L-prolyl,L-piperidine-2-carbonyl, N-propyl-D-piperidine-2-carbonyl,D-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl,N-methyl-[2,2,5,5-tetramethyl]-L-thiazolidine-2-carbonyl,N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2-cyclopropylglycyl,N,N-dimethyl-D-2-ethyl-2-phenylglycyl, N,N-dimethyl-L-2-ethyl-2-phenylglycyl, D-prolyl, N-methyl-D-prolyl,N,N-dimethyl-2-(2-fluorophenyl-glycyl,1-aza-[3,3,0]bicyclooctyl-5-carbonyl,N,N-dimethyl-2-[4-fluoro]phenyl-glycyl,N-methyl-[2,2,5,5-tetramethyl]-thiazolidine-2-carbonyl,2-(R,S)-ethyl-2-phenylglycyl, D,L-2-aminoindane-1-carbonyl,N,N-dimethyl-2-(R,S)-methyl-2-phenylglycyl,2-[N,N-dimethylamino]indane-2-carbonyl,5-[N,N-dimethylamino]-5,6,7,8-tetrahydro-naphthalene-5-carbonyl,N-isopropyl-2-(R,S)-ethyl-2-phenylglycyl,1-[N,N-dimethylamino]indane-2-carbonyl,N,N-dimethyl-2-propyl-2-phenylglycyl,N,N-dimethyl-2-[4-methoxy]phenyl-glycyl, N-methyl-3-hydroxy-D,L-valyl,N,N-dimethyl-D,L-2-isopropyl-2-phenylglycyl,N-methylpiperidine-2-carbonyl, N-methyl-L-prolyl,N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl,N-methylazetidine-2-carbonyl, N-isopropylazetidine-2-carbonyl,N,N-dimethyl-[O-methyl]seryl, N,N-dimethyl-[O-methyl]threonyl,N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl,1-[N,N-dimethylamino]cyclohexyl-1-carbonyl,1-[N,N-dimethylamino]cyclopentyl-1-carbonyl and1,2,3,4-tetrahydroisoquinoline-3-carbonyl; B is an amino acid residueselected from the group consisting of valyl, isoleucyl and2-tert-butylglycyl; D is an amino acid residue selected from the groupconsisting of N-methylvalyl, N-methylisoleucyl andN-methyl-L-2-t-butylglycyl; E and F are each an amino acid residueindependently selected from the group consisting of prolyl,thiaprolyl,homoprolyl, hydroxyprolyl, 3,4-didehydroprolyl,4-fluoroprolyl, and 3-methylprolyl; and L is an alkoxy group or an aminogroup of the formula R¹ _(l) --N--R² _(l), wherein R¹ _(l) and R² _(l)are independently selected from the group consisting of hydrogen,alkoxy, hydroxy, alkyl and alkylaryl.
 37. A compound of the formula

    A-B-D-E-F-L,

wherein A is an amino acid derivative selected from the group consistingof D-N-methyl-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl,N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2-cyclopropyl-glycyl,N-methyl-D-prolyl, 1-aza-[3,3,0]bicyclooctyl-5-carbonyl,N-methyl-[2,2,5,5-tetramethyl]-thiazolidine-2-carbonyl,2-(R,S)-ethyl-2-phenylglycyl, D,L-1-aminoindane-1-carbonyl,N,N-dimethyl-2-(R,S)-methyl-2-phenylglycyl,5-[N,N-dimethylamino]-5,6,7,8-tetrahydro-naphthalene-5-carbonyl,1-[N,N-dimethylamino]indane-2-carbonyl,N,N-dimethyl-2-propyl-2-phenylglycyl, N-methyl-3-hydroxy-D,L-valyl,N,N-dimethyl-D,L-2-isopropyl-2-phenylglycyl,N-methyl-piperidine-2-carbonyl, N-methyl-D,L-prolyl,N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl,N-ethylazetidine-2-carbonyl, N-isopropylazetidine-2-carbonyl,N,N-dimethyl-[O-methyl]seryl,1-[N,N-dimethylamino]cyclohexyl-1-carbonyl,N,N-dimethyl-D-2-ethyl-2-phenylglycyl,N,N-dimethyl-L-2-ethyl-2-phenylglycyl, and1-[N,N-dimethylamino]cyclopentyl-1-carbonyl; B is valyl; D isN-methylvalyl; E and F are each prolyl; and L is a C₁ -C₆ -alkoxy groupor an amino group of the formula R¹ _(l) --N--R² _(l), wherein R¹ _(l)and R² _(l) are independently selected from the group consisting ofhydrogen, C₁ -C₆ -alkoxy, hydroxy, normal, cyclic or branched C₁ -C₁₀-alkyl, and phenylalkyl.
 38. A method for treating cancer in a mammal,comprising administering to the mammal a therapeutically effectiveamount of a compound of claim
 1. 39. The method of claim 38 wherein themammal is a human.